- Miguel Quintela-Fandino
- Daniel Shao Weng Tan
- Timothy A. Yap
- Nicholas McGranahan
70O - Relationships between lenvatinib plasma concentration and toxicity in Japanese cancer patients
- Reiko A. Makihara
- Reiko A. Makihara
- Shoko N. Narita
- Noboru Yamamoto
- Jun Sato
- Shuji Murakami
- Yasushi Goto
- Shintaro Kanda
- Yutaka Fujiwara
- Hidehito Horinouchi
- Taku Tsukamoto
- Hironobu Hashimoto
- Yoshinori Makino
- Yuichiro Ohe
- Masakazu Yamaguchi
Abstract
Background
Lenvatinib is an oral, multi-targeting inhibitor for VEGFR, FGFR, PDGFR, KIT and RET. This agent has been approved for thyroid cancer with a recommended dosage of 24-mg QD and for hepato-cellular carcinoma with 8 or 12-mg QD. Although lenvatinib has substantial anti-tumor activity for thyroid cancer as well as other solid tumors including colorectal cancer and non-small cell lung cancer, dose modification is frequently required due to proteinuria, decreased weight, anorexia, hand-foot syndrome and some other gastro-intestinal toxicities. Dose individualization with close plasma concentration monitoring could contribute to address these issues in routine clinical practice.
Methods
Patients, who received lenvatinib as practical treatment setting, were enrolled in our prospective pharmacokinetic individualized study. Plasma trough concentration as well as dried plasma spot (DPS) samples were obtained from all enrolled patients. Lenvatinib plasma concentrations were measured by in-house LC/MS/MS, and investigated with the correlation with toxicities by lenvatinib. The study protocol was approved by our institutional review board and informed consent was obtained from all patients.
Results
From Jun 2017 to Jun 2018, 17 patients (13 thymic cancer, 1 thyroid cancer and 3 lung cancer with RET-fusion) were enrolled. At a dosage of 24-mg QD, the geometric mean plasma lenvatinib trough concentrations at steady state was averaged at 65.1 (range 39.3-105.4) ng/mL. All enrolled patients had required a dose reduction due to AEs, and final lenvatinib doses with acceptable tolerability were 20 mg in 3, 14 mg in 5, 10 mg in 4, 8 mg in 3, and 4 mg in 2 patients, respectively. The geometric mean plasma lenvatinib trough concentrations with final dosage was 52.6 (range 25.8-107.4) ng/mL. All DPS samples showed comparable concentrations to plasma samples.
Conclusions
The plasma lenvatinib trough concentration with final dosage adjusted by AEs was < 60 ng/mL. Therapeutic drug monitoring of lenvatinib could minimize unacceptable AEs and contribute individualized dosing. Also, we firstly confirmed the feasibility of lenvatinib DPS assay with high compatibility with plasma concentrations.
Legal entity responsible for the study
The authors.
Funding
Has not received any funding.
Disclosure
N. Yamamoto, Y. Fujiwara: Eisai Co., Ltd. All other authors have declared no conflicts of interest.
71O - Phase 1 extension study of ETC-159 an oral PORCN inhibitor administered with bone protective treatment, in patients with advanced solid tumours.
- David Tan
- David Tan
- Matthew Ng
- Vivek Subbiah
- Wells Messersmith
- Vincenzo Teneggi
- Veronica Diermayr
- Kantharaj Ethirajulu
- Pauline Yeo
- Bong Hwa Gan
- Lay Hoon Lee
- Stephanie Blanchard
- Ranjani Nellore
- Maryam Yasin
- Dhananjay Umrani
- May Ann Lee
- Jeffrey Hill
- Babita Madan
- David Virshup
- Alex Matter
Abstract
Background
Aberrant Wnt pathway signalling is seen in several cancers. ETC-159 is a selective small molecule inhibitor of porcupine. During dose escalation in patients (pts) with advanced solid tumours, the maximum tolerated dose (MTD) of ETC-159 was 30 mg every other day (qod) with dose-limiting toxicities (DLTs) of compression fractures and hyperbilirubinaemia, and toxicity of concern of elevated serum β-CTX (ASCO 2017, Abstract #2584). We report the interim results of ETC-159 dose escalation with prophylactic denosumab and biomarker analyses.
Methods
Open-label, multi-centre study to assess safety, MTD, pharmacokinetics (PK) and pharmacodynamics (PD) of ETC-159 given orally, qod at the dose of 16 and 24 mg, with denosumab s.c. once every 28d during the first 2 cycles. Bone turnover was assessed in serum and via radiology. PD was tested using Axin2 mRNA levels in hair follicles (HFs). Immune markers were analysed in pre- and post-dose biopsies. Dose escalation and DLT incidence assessment were assisted by a Bayesian approach, with a DLT period of 28d.
Results
As of April 2018, 5 pts were treated at 16 mg and 3 at 24 mg. 50% were female, median age (range) 55.5 yr (47-71). There was one DLT (grade 2 dysgeusia). Adverse events (>20%) were: dysgeusia (62%), fatigue (37%), weight loss (37%), back pain (37%), headache (37%), vomiting (25%), nausea (25%) and abdominal pain (25%). At the dose of 16 mg ETC-159 showed inter-patient PK variability, with a mean t ½ of ∼15h (d1) and ∼37h (d15). Serum β-CTX reduction from pre-dose was seen in 6/8 pts. In 1 pt serum β-CTX increased to > 1000 pg/mL (with reduction of bone mineral density) and reduced after ETC-159 discontinuation; in 1 pt β-CTX was not assessed due to early discontinuation. 4 pts withdrew for progressive disease,1 pt for DLT, 1pt for consent withdrawal and 2 pts are ongoing. Decreased Axin2 mRNA was seen in HFs and a 2-fold increase of the ratio of tumour infiltrating CD8+/FOXP3+ T-cells was seen in the tumour.
Conclusions
ETC-159 with prophylactic denosumab is safe; there are no compression fractures and β-CTX decreases in most pts. ETC-159 has PD activity and increases immune infiltration. ETC-159 dosing is ongoing at 24 mg.
Clinical trial identification
NCT02521844.
Legal entity responsible for the study
A*STAR, D3 (Drug Discovery and Development), Singapore.
Funding
A*STAR, D3 (Drug Discovery and Development), Singapore.
Disclosure
V. Teneggi, V. Diermayr, K. Ethirajulu, P. Yeo, B.H. Gan, L.H. Lee, S. Blanchard, R. Nellore, M. Yasin, A. Matter, D. Umrani: Employment: D3, sponsor of the study. All other authors have declared no conflicts of interest.
72O - Addition of durvalumab (Dur) upon progression to bevacizumab (Bev) maintenance in advanced HER2-negative (HERNEG) breast cancer (BC): safety, efficacy and biomarkers.
- Miguel Quintela-Fandino
- Miguel Quintela-Fandino
- Luis M. Manso Sànchez
- Esther Holgado Martín
- Maria C. Moreno
- Serafin Morales Murillo
- Begona Bermejo De Las Heras
- Diego Malon Gimenez
- Ramon Colomer Bosch
- Lucia Gonzalez Cortijo
- Javier Hornedo
- Silvana Mouron
- Manuel Muñoz
- Sara Escudero
- Raquel Blanco
- Santos Mañes
Abstract
Background
As opposed to other malignancies, immunotherapy has yielded limited efficacy in BC. We have found in animal models of HERNEG BC that chronic hypoxia secondary to prolonged Bev was associated to anti-tumor immune suppression and tumor PD-L1 upregulation. These events rendered HERNEG BC animal models sensitive to PD-L1 blockade in combination with Bev. We sought to explore this concept in the clinics in a pilot phase IB trial in HERNEG BC patients with disease progression (PD) on Bev maintenance by adding the anti-PD-L1 antibody Dur.
Methods
HER2NEG metastatic patients with PD to Bev maintenance for a minimum of six weeks after first-line taxane+Bev were enrolled. Dur (10 mg/kg q14d) was added to maintenance Bev (10 mg/kg q14d). Patients were evaluated every 56 days (iRECIST). Before the first Dur dose and every 4 weeks until PD, peripheral-blood mononuclear cells (PBMCs) were phenotyped in order to monitor 24 lymphoid and non-neutrophil myeloid subpopulations. The primary endpoint was PFS time. Secondary endpoints were toxicity assessed with NCI CTC AE V. 4.03 and relative changes (%) in PBMCs subpopulations.
Results
24 patients were accrued. Median age was 56 and 12 (50%) patients were triple-negative. Median (range) Bev exposure during maintenance before entering trial was 11 (6-22) months. Grade 3 toxicity included pneumonitis (1 patient) and hypertension (2 patients), related to Dur and Bev respectively. Grade 1/ 2 toxicity was observed in 18 (66%) patients. Median PFS was 76 days; 8 patients (33%) are still in the trial. Four patients have not experienced PD yet after 100+ days. Best response was SD (9 patients, 38%). Sixty-two per cent of the patients reached the first evaluation with SD; all of them had a 1.2- to 3.5-fold increase in CD8 effector memory T-cells (CD8EM) in PBMCs after the first Dur dose. All but one patient that experienced PD in the first evaluation had no change or a decrease up to 3.2-fold in CD8EM in PBMCs.
Conclusions
Bev maintenance could expand the therapeutic niche of immunotherapy in HERNEG BC, evidenced by the efficacy of Dur in this context at low toxicity cost in this phase 1B study. Patients experiencing benefit showed detectable changes in CD8EM in PBMCs.
Clinical trial identification
NCT02802098.
Legal entity responsible for the study
Fundacion CRIS Contra el Cancer.
Funding
AstraZeneca.
Disclosure
M. Quintela-Fandino: Research funds: AstraZeneca. All other authors have declared no conflicts of interest.
Discussion
- Daniel Shao Weng Tan
- Timothy A. Yap
- Daniel Shao Weng Tan
- Timothy A. Yap
367O - Parallel identification and profiling of tumour antigen-specific T cells for biomarker discovery by mass cytometry
- Michael Fehlings
- Michael Fehlings
- Evan W. Newell
Abstract
Background
Immunotherapy recent successes have opened new avenues for the treatment of cancer and the presence of tumor-specific CD8+ T cells in tumor-bearing individuals offer a promising therapeutic target. However, the detection and profiling of such T cells are challenging due to the need to detect rare antigen-specific T cell subpopulations in patient samples that are limited in size thus making it difficult to exploit these parameters for predictive signatures of clinical response.
Methods
We leverage the high-dimensional immune profiling capabilities of mass cytometry (a.k.a. cytometry by the time of flight, CyTOF) combined with a unique technology for the identification and simultaneous characterization of rare antigen-specific T-cell subsets.
Results
We demonstrate the feasibility of this technology by using a murine in vivo model that is susceptible to checkpoint blockade immunotherapy. Applying this technology to tumor-infiltrating lymphocytes from human cancer samples facilitated the identification of antigen-specific T cells in individual patients. Interestingly, the majority of patient-derived tumor infiltrates consisted of tumor-unrelated T-cells characterized by a diverse phenotype. Strikingly, the expression of CD39 was absent from these bystander cells, suggesting that CD39 could be a useful biomarker for the identification of putative tumor-reactive T cells.
Conclusions
Using a unique target discovery and high-dimensional immune profiling platform to probe tumor-reactive T cells in cancer patients will facilitate further translational studies assessing the relationship between specific T cell responses and clinical outcome as well as the development of novel diagnostic biomarkers and immunotherapy strategies.
Legal entity responsible for the study
A-STAR/SIgN immunomonitoring platform.
Funding
A-STAR/SIgN core funding and A-STAR/SIgN immunomonitoring platform funding assigned to E.W.N. as well as NMRC/CSA- INV/0001/2014 grant (GIS) and core A-STAR/GIS funding to I.B.T. and the lung TCR grant NMRC/TCR/007-NCC/2013.
Disclosure
F. Michael, E.W. Newell: Co-founder of Immunoscape.
368O - Tumor mutation index as biomarker for responsive stratification on multi-targeted TKI Anlotinib: an ALTER-0303 companion diagnostic study
- Jun Lu
- Jun Lu
- Wei Zhang
- Bo Yan
- Hua Li
- Lele Zhang
- Yu Dong
- Jie Qian
- Shuyuan Wang
- Bo Zhang
- Jun Wu
- Xiaodong Zhao
- Yizhuo Zhao
- Baohui Han
Abstract
Background
To date, there has been no suitable biomarker for response stratification upon multi-targeted anti-tumor drugs. Anlotinib, one of the multi-targeted anti-tumor drugs, which has been effectively administrated in Non-Small Cell Lung Cancer (NSCLC) at 3rd line, also suffers from the unavailability of suitable biomarker for its response stratification. Evaluation of the mutation determinants of plasma cell free DNA (cfDNA) and circulating tumor DNA (ctDNA) for stratifying anlotinib responders has not yet been demonstrated.
Methods
We used a tumor-specific targeted capture to profile the cfDNA and ctDNA of 80 ALTER-0303 (Evaluating NSCLC clinical anti-tumor efficacy through anlotinib therapy) study participants. We identified three predictors, germline and somatic mutation burden (G+S MB), nonsynonymous and synonymous mutation burden (N+S MB) and unfavorable mutation score (UMS)) of cfDNA and ctDNA profiling, and analysed the correlations between mutational landscape and anlotinib response. Through integrating the merits and defects of three independent predictors, we established a prediction model of tumor mutation index (TMI) and identified the patients who are very likely to obtain more benefit from anlotinib therapy.
Results
Our data indicated that the patients harboring fewer mutations received more benefit from anlotinib therapy. TMI is an effective biomarker for anlotinib responsive stratification upon discovery cohort (n = 62, cutoff = 60, median PFS: 210 days vs 126 days; p = 0.0008; AUC = 0.76, 95% CI: 0.62 to 0.89) and validation cohort (n = 80, cutoff = 60, median PFS: 210 days vs 127 days; p = 0.0006). Furthermore, we identified IDH1 mutation as an unfavorable factor to anlotinib therapy, and integrative analysis of TMI and IDH1 mutation resulted in a more promising anlotinib responsive stratification (median PFS: 244 days vs 87 days; p < 0.0001; AUC = 0.90, 95% CI: 0.82 to 0.97).
Conclusions
This study provides a biomarker of TMI to stratify underlying anlotinib responders via a non-invasive approach and can thus potentially improve clinical outcome for anlotinib therapy in NSCLC patients at 3rd line.
Clinical trial identification
NCT02388919.
Legal entity responsible for the study
Shanghai Chest Hospital.
Funding
This work was supported by the program of system biomedicine innovation center from Shanghai Jiao Tong University (Project No. 15ZH4009); the key program of translational medicine from Shanghai Jiao Tong University School of Medicine (Project No. 15ZH1008); National Natural Science Foundation of China (Project No. 81673015); and the project of Science and Technology Commission of Shanghai Municipality (Project No. 16140902700).
Disclosure
All authors have declared no conflicts of interest.
369O - Biomarker-integrated study of single agent targeting molecular alterations of PI3KCA, MET, ALK, ROS1, KRAS, NRAS or BRAF in advanced NSCLC: Ph2 umbrella trial in China (CTONG1505)
- Qing Zhou
- Qing Zhou
- Xu-Chao Zhang
- Hai-Yan Tu
- Bin Gan
- Bin-Chao Wang
- Chong-Rui Xu
- Hua-Jun Chen
- Ming-Ying Zheng
- Zhen Wang
- Xiao-Yan Bai
- Yue-Li Sun
- Andrea Myers
- Xueting Lv
- Yajnaseni Chakrabcorti
- Sylvia Zhao
- Jin-Ji Yang
- Yi-Long Wu
Abstract
Background
Several genetically altered signaling pathways have been profiled in NSCLC, enabling advanced management of NSCLC using targeted therapies. This study investigated the therapeutic spectrum of NSCLC with uncommon molecular alterations by allocating patients to treatment arms based on molecular aberrations, alpelisib for PIK3CA mutation/amplification, capmatinib for MET IHC overexpression/amplification, ceritinib for ALK or ROS1 rearrangement, and binimetinib for KRAS, NRAS or BRAF mutation.
Methods
The study was based on the umbrella design. Key objectives: investigate the feasibility of one trial for different agents based on biomarker-integrated analysis, assess anti-tumor activity, characterize safety, tolerability and PK profiles of individual agents. Key eligibility criteria: age ≥18 years; ECOG PS ≤ 2; failed prior treatment/unsuitable for chemotherapy. Documentation of locally determined molecular alterations of PI3KCA, MET, ALK, KRAS, NRAS or BRAF before treatment allocation was required.
Results
Sixty-six patients with advNSCLC were enrolled (median age 58 years; 65.2% male: alpelisib, n = 2; capmatinib, n = 16; ceritinib, n = 26; binimetinib, n = 22). As of Feb 28, 2018, 10 patients in ceritinib and 2 in binimetinib arm were ongoing. Twenty-four patients had confirmed partial responses (36.4%): alpelisib, 0%; capmatinib, 18.8%; ceritinib, 73.1%; binimetinib, 9.1% (Figure). Highest mPFS (14.4 months) was in ceritinib arm. Most common treatment-related AEs: alpelisib: malaise, hyperglycemia, dysgeusia; capmatinib: nausea, anemia, peripheral oedema, decreased appetite; ceritinib: diarrhea, vomiting, ALT/AST elevation; binimetinib: mouth ulceration, AST, blood CPK increased, rash. Majority of AEs were grade 1/2.
Conclusions
Objective responses/tumor shrinkage were observed in the study; highest ORR and mPFS were observed with ceritinib despite different patient numbers in 4 arms. All treatments were well tolerated; no new safety signals were observed. This study demonstrated the feasibility of an umbrella trial and importance of precision medicine in the management of advNSCLC with uncommon molecular alterations.
Clinical trial identification
NCT02276027.
Legal entity responsible for the study
Chinese Thoracic Oncology Group.
Funding
Novartis.
Disclosure
A. Myers, X. Lv, Y. Chakrabcorti: Novartis. All other authors have declared no conflicts of interest.
Discussion
- Miguel Quintela-Fandino
- Nicholas McGranahan
- Miguel Quintela-Fandino
- Nicholas McGranahan