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Investigational immunotherapy

968P - Association between use of antibiotics (ATB) and clinical outcomes with tislelizumab (tisle) monotherapy

Presentation Number
968P
Speakers
  • Zheng-Gang Ren (Shanghai, China)

Abstract

Background

Immune checkpoint inhibitors (ICIs) have changed the therapeutic landscape of many cancers but ICI efficacy varies greatly. Retrospective analyses showed ATB may have a negative impact on ICI efficacy. However, heterogeneous results induced by ATB observed across studies may be due to population diversity, different definitions of ATB use, limited sample size, etc.

Methods

Data from 5 tisle monotherapy studies were analysed. Patients were dichotomized by timing of IV/oral ATB use; ±30 days of Day 1 tisle treatment was ‘ATB+’, otherwise ‘ATB-’. Propensity score weighting was employed to correct for bias from unbalanced baseline characteristics. Survival probability was estimated by the Kaplan–Meier method and compared by log-rank test. Cox model of overall survival (OS) was used to compute hazard ratio (HR) and 95% confidence interval (CI). Landmark analysis was conducted to explore the association of ATB use and OS across time to mitigate guarantee-time bias.

Results

217/1183 (18%) patients received ATB. OS was significantly decreased in the ATB+ group vs the ATB- group (HR: 1.5; 95% CI: 1.3–1.9, p<0.0001). In the ATB+ group, OS was significantly decreased with prophylactic vs non-prophylactic ATB treatment (HR: 2.5; 95% CI: 1.5–4, p<0.0001). A significant association between ATB use and decreased OS was shown in patients with esophageal squamous cell carcinoma (ESCC) (HR: 3.0; 95% CI: 1.3–7.2, p<0.01), hepatocellular carcinoma (HCC) (HR: 1.8; 95% CI: 1.1–2.9, p<0.01) and urothelial carcinoma (UC) (HR: 2.3; 95% CI: 1.3–3.9, p<0.001). A worse trend in OS was observed for non-small cell lung cancer (NSCLC) (HR: 1.6; 95% CI: 0.74–3.6, p=0.26). Landmark analysis identified the time intervals, as related to Day 1 of tisle treatment, when ATB use had a significant negative impact on OS per tumor type: Day -15–45 for ESCC, Day 19–45 for HCC, and Day -5–133 for UC. No significant time interval emerged in NSCLC.

Conclusions

In this pooled analysis, a negative association was observed between ATB use during tisle treatment and OS in a pooled population and in ESCC, HCC and UC. Time intervals in which ATB use had a significant negative impact on OS were identified per indication. Prophylactic ATB use showed a poorer OS outcome vs non-prophylactic ATB use.

Clinical trial identification

Pooled analysis of the following trials: BGB-A317-001; NCT02407990 BGB-A317-102; CTR20160872 BGB-A317-203; NCT03209973 BGB-A317-204; CTR20170071 BGB-A317-208; NCT03419897.

Editorial acknowledgement

Third-party medical writing assistance, under the direction of the authors, was provided by Jenny Feehan, BSc, of Ashfield MedComms, and was funded by BeiGene, Ltd.

Legal entity responsible for the study

BeiGene, Ltd.

Funding

BeiGene, Ltd.

Disclosure

Z. Ren: Financial Interests, Other, Honoraria: BeiGene, AstraZeneca, F. Hffmann-La Roche, and Merck Sharp & Dohme; Financial Interests, Advisory Role: AstraZeneca, F. Hoffmann-La Roche Ltd, Merck. Y. Gao: Financial Interests, Full or part-time Employment: BeiGene, Ltd.; Financial Interests, Stocks/Shares: BeiGene, Ltd.; Financial Interests, Other, Travel, Accommodations, Expenses: BeiGene, Ltd. C. Wei: Financial Interests, Full or part-time Employment: BeiGene, Ltd. X. Li: Financial Interests, Full or part-time Employment: BeiGene, Ltd. S. Liu: Financial Interests, Full or part-time Employment: BeiGene, Ltd. J. Zhang: Financial Interests, Full or part-time Employment: BeiGene, Ltd. L. Wang: Financial Interests, Full or part-time Employment: BeiGene, Ltd. Y. Wu: Non-Financial Interests, Sponsor/Funding: AstraZeneca, Boehringer Ingelheim, BMS, Hengrui, Pfizer and Roche; Non-Financial Interests, Advisory Role: AstraZeneca, Boehringer Ingelheim, Novartis, Merck, MSD, Roche and Takeda; Financial Interests, Other, Honoraria: AstraZeneca, Boehringer Ingelheim, BMS, Eli Lilly, Hengrui, MSD, Pfizer, Roche and Sanofi.

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Investigational immunotherapy

971P - Is there a clinical benefit of nivolumab + ipilimumab in patients older than 75 years with advanced solid tumors?

Presentation Number
971P
Speakers
  • Thierry Landre (Sevran, France)

Abstract

Background

Combination therapy with nivolumab + ipilimumab (Nivo+Ipi) has been widely used for clinical treatment in recent years, which has a better survival benefit. However, not all patients can derive clinical benefit from this combination immunotherapy.

Methods

We performed an age subgroup analysis of published randomized control trials concerning "Nivo+Ipi" versus standard therapy in patients with advanced solid tumours. Overall Survival (OS) among the elderly (≥ 75 years) was compared with that of younger patients (≥ 65 to < 75 years). Hazard ratios (HRs) with their 95% confidence interval (CI) were collected from the studies and pooled. A fixed-effect model was used.

Results

Few studies have been published corresponding to our inclusion criteria. Two studies (CheckMate 9LA and CheckMate 227) assessed "Nivo+Ipi" in Non-Small Cell Lung Cancer (NSCLC), one study (CheckMate 214) assessed "Nivo+Ipi" in Renal-Cell Carcinoma (RCC); the last one (CheckMate 743) assessed "Nivo+Ipi" in Malignant Pleural Mesothelioma. Our pooled-analysis included 373 patients older than 75 years (308 with thoracic cancers and 65 with RCC) and 1140 patients between 65 and 75 years (882 thoracic cancers and 258 RCC). All patients were mostly men (68%), with good Performance Status (0 or 1). For patients ≥75 years, OS of the "Nivo+Ipi" arm was similar to that of the control arm (HR = 0.98; 95% CI 0.76-1.26; p = 0.86). Conversely, among younger patients (≥65 to < 75 years), a statistically significant OS benefit was observed with "Nivo+Ipi" (HR = 0.74; 95 % CI 0.64-0.85; p < 0.0001). However, the difference observed between subgroups was not statistically significant (p= 0.06).

Conclusions

Due to the low number of elderly patients in clinical trials, there is an uncertainty to prescribe the combination "Nivo+Ipi" for older population (≥75 years). Further studies are warranted.

Legal entity responsible for the study

T. Landre.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

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Investigational immunotherapy

973P - A phase II study of PDR001 among patients with recurrent and/or metastatic esophageal squamous cell carcinoma: An interim analysis of KM-12

Presentation Number
973P
Speakers
  • Dong Ki Lee (Seoul, Korea, Republic of)

Abstract

Background

Programmed cell death protein 1 (PD-1) inhibitors emerged as a promising treatment option for esophageal cancer refractory to standard treatment. PDR001 (spartalizumab) is a humanized IgG4 monoclonal antibody targeting PD-1. We report the results of a single-arm phase II study of PDR001 in the treatment of esophageal squamous cell carcinoma (ESCC) in Korea.

Methods

Inclusion criteria were histologically proven ESCC with a measurable lesion refractory or intolerant to standard therapy. We collected the information regarding patients’ baseline characteristics and responses measured by Response Evaluation Criteria in Solid Tumours version 1.1. The primary endpoint was the overall response rate (ORR). Secondary endpoints included disease control rate (DCR), progression-free survival, overall survival, and duration of response.

Results

Forty-nine patients were screened and a total of 44 eligible patients with ESCC were enrolled. At the data cut-off, the response of 3 patients was pending. The ORR was 18.2% (95% confidence interval [CI], 9.3% to 32.2%), and DCR was 56.8% (95% CI, 42.2% to 70.3%). The most frequent treatment-related adverse events (TRAEs) were grade 1 or 2 hypothyroidism (n = 4) and rash (n = 4). Grade 3 TRAEs included amylase elevation (n = 1), dry mouth (n = 1), sore throat (n = 1), and myalgia (n = 1) but none of them led to treatment delay or discontinuation. No grade 4 or greater TRAEs were reported.

Conclusions

The study is ongoing and PDR001 showed modest clinical benefits with manageable toxicity in refractory ESCC. The efficacy and safety in this population were consistent with those of previous PD-1 inhibitor trials. Biomarker analysis including programmed death ligand 1 (PD-L1) expression are planned.

Clinical trial identification

NCT03785496.

Editorial acknowledgement

The study was supported by K-MASTER project. Novartis provided PDR001.

Legal entity responsible for the study

The authors.

Funding

Novartis.

Disclosure

All authors have declared no conflicts of interest.

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Investigational immunotherapy

1034TiP - ARTISTRY-6: Nemvaleukin alfa monotherapy in patients with advanced mucosal and cutaneous melanoma

Presentation Number
1034TiP
Speakers
  • Richard D. Carvajal (New York, NY, United States of America)

Abstract

Background

Despite improved outcomes for melanoma patients with the introduction of checkpoint inhibitors (CPIs), ∼50% of patients do not respond. A subset of responders ultimately progress and have limited treatment options, underscoring a high unmet need for novel treatments with durable benefit. Patients with mucosal melanoma exhibit response rates and progression-free survival times ∼2 times lower than those with cutaneous melanoma. Nemvaleukin alfa (nemvaleukin, ALKS 4230) is a novel, engineered cytokine that selectively binds the intermediate-affinity interleukin-2 receptor complex to preferentially activate CD8+ T and NK cells with minimal expansion of regulatory T-cells. Nemvaleukin has been granted orphan drug designation for the treatment of mucosal melanoma by the FDA. In ARTISTRY-1, intravenous (IV) recommended phase II dose (RP2D) of 6 μg/kg nemvaleukin monotherapy demonstrated durable antitumor activity in patients with advanced melanoma, including mucosal melanoma, previously treated with a CPI. In ARTISTRY-2, subcutaneous (SC) RP2D of 3 mg q7d was identified demonstrating pharmacodynamic effects consistent with IV. Data support further evaluation of nemvaleukin monotherapy among patients with advanced mucosal and cutaneous melanoma.

Trial design

ARTISTRY-6 is a phase II, global, multicenter, open-label study. Eligible patients have had prior treatment with an anti–PD-(L)1 therapy with or without anti–CTLA-4 therapy and have an ECOG performance status of 0 or 1, adequate hematologic reserve and hepatic and renal function. Patients with advanced cutaneous (cohort 1) and mucosal (cohort 2) melanoma will receive nemvaleukin at the SC and IV R2PD, respectively. Patients will receive nemvaleukin until progression or intolerable toxicity. The primary objective is to evaluate the antitumor activity of nemvaleukin monotherapy. Additional objectives include the evaluation of safety, health-related quality of life, predictive biomarkers, pharmacokinetics, immunogenicity, and pharmacodynamic effects.

Clinical trial identification

NCT04830124.

Editorial acknowledgement

Medical writing and editorial support was provided by Melanie J. Jardim, PhD, of Parexel International.

Legal entity responsible for the study

Alkermes, Inc.

Funding

Alkermes, Inc.

Disclosure

R.D. Carvajal: Financial Interests, Personal, Advisory Role: BMS; Financial Interests, Personal, Advisory Role: Castle Biosciences; Financial Interests, Personal, Advisory Role: Compugen; Financial Interests, Personal, Advisory Role: Foundation Medicine; Financial Interests, Personal, Advisory Role: Immunocore; Financial Interests, Personal, Advisory Role: I-Mab; Financial Interests, Personal, Advisory Role: Incyte; Financial Interests, Personal, Advisory Role: Merck; Financial Interests, Personal, Advisory Role: Roche/Genentech; Financial Interests, Personal, Advisory Role: Pure Tech Health; Financial Interests, Personal, Advisory Role: Sanofi Genzyme; Financial Interests, Personal, Advisory Role: Sorrento Therapeutics; Financial Interests, Personal, Advisory Board: Aura Biosciences; Financial Interests, Personal, Advisory Board: Chimeron; Financial Interests, Personal, Advisory Board: Rgenix; Financial Interests, Institutional, Funding: Amgen; Financial Interests, Institutional, Funding: Astellis; Financial Interests, Institutional, Funding: AstraZeneca; Financial Interests, Institutional, Funding: Bayer; Financial Interests, Institutional, Funding: Bellicum; Financial Interests, Institutional, Funding: BMS; Financial Interests, Institutional, Funding: Corvus; Financial Interests, Institutional, Funding: Eli Lilly; Financial Interests, Institutional, Funding: Immunocore; Financial Interests, Institutional, Funding: Incyte; Financial Interests, Institutional, Funding: Macrogenics; Financial Interests, Institutional, Funding: Merck; Financial Interests, Institutional, Funding: Mirati; Financial Interests, Institutional, Funding: Novartis; Financial Interests, Institutional, Funding: Pfizer; Financial Interests, Institutional, Funding: Plexxikon; Financial Interests, Institutional, Funding: Roche/Genentech. J.S. Weber: Financial Interests, Personal, Advisory Board: BMS; Financial Interests, Personal, Advisory Board: Merck; Financial Interests, Personal, Advisory Board: GSK; Financial Interests, Personal, Advisory Board: Genentech; Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Personal, Advisory Board: Regeneron; Financial Interests, Personal, Advisory Board, SAB member: Cytomx; Financial Interests, Personal, Member, SAB member: Sellas; Financial Interests, Personal, Member, SAB member: Neximmune; Financial Interests, Personal, Advisory Board: Idera; Financial Interests, Personal, Advisory Board: OncoSec; Financial Interests, Personal, Advisory Board: Incyte; Financial Interests, Personal, Advisory Board: Pfizer; Financial Interests, Personal, Member, SAB member: Celldex; Financial Interests, Personal, Member, SAB member: Protean; Financial Interests, Personal, Member, SAB member: Evaxion; Financial Interests, Personal, Advisory Board: Editas; Financial Interests, Personal, Member, DSMB: Ultimovacs; Financial Interests, Personal, Advisory Board: Immunocore; Financial Interests, Personal, Advisory Board, SAB Member: Biond; Financial Interests, Personal, Stocks/Shares: Neximmune; Financial Interests, Personal, Stocks/Shares: CytoMx; Financial Interests, Personal, Stocks/Shares: Biond; Financial Interests, Personal, Stocks/Shares: Celldex; Financial Interests, Personal, Royalties, Named on a patent from Moffitt Cancer Center: Iovance; Financial Interests, Institutional, Research Grant: BMS; Financial Interests, Institutional, Research Grant: Merck; Financial Interests, Institutional, Research Grant: Incyte; Financial Interests, Institutional, Research Grant: GSK; Financial Interests, Institutional, Research Grant: Moderna. A.Z. Dudek: Financial Interests, Personal, Advisory Role: HiberCell; Financial Interests, Personal, Member of the Board of Directors, Chief Medical Officer: Vanquish Oncology; Financial Interests, Personal, Member of the Board of Directors, Chief Medical Officer: TTC Oncology; Financial Interests, Personal, Member of the Board of Directors, Chief Medical Officer: IGF Oncology; Financial Interests, Personal, Member of the Board of Directors, Chief Medical Officer: Squarex; Financial Interests, Personal, Member of the Board of Directors: Martell Diagnostic Laboratory; Financial Interests, Personal, Stocks/Shares: Vanquish Oncology; Financial Interests, Personal, Stocks/Shares: IFG Oncology; Financial Interests, Personal, Stocks/Shares: TTC Oncology; Financial Interests, Personal, Stocks/Shares: Martell Diagnostic Laboratory; Financial Interests, Personal, Stocks/Shares: Squarex; Financial Interests, Personal, Stocks/Shares: Luminary Therapeutics; Non-Financial Interests, Personal, Principal Investigator: Hiber Cell; Financial Interests, Personal, Leadership Role: Midwest Melanoma Partnership. O. Hamid: Financial Interests, Personal, Advisory Role: Aduro; Financial Interests, Personal, Advisory Role: Akeso; Financial Interests, Personal, Advisory Role: Amgen; Financial Interests, Personal, Advisory Role: Beigene; Financial Interests, Personal, Invited Speaker, Consultant: BMS; Financial Interests, Personal, Advisory Role: Roche Genentech; Financial Interests, Personal, Advisory Role: GSK; Financial Interests, Personal, Advisory Role: Immunocore; Financial Interests, Personal, Advisory Role: Incyte; Financial Interests, Personal, Advisory Role: Janssen; Financial Interests, Personal, Advisory Role: Merck; Financial Interests, Personal, Advisory Role: Nextcure; Financial Interests, Personal, Invited Speaker, Consultant: Novartis; Financial Interests, Personal, Invited Speaker, Consultant: Pfizer; Financial Interests, Personal, Invited Speaker, Consultant: Sanofi; Financial Interests, Personal, Invited Speaker, Consultant: Regeneron; Financial Interests, Personal, Advisory Role: SeaGen; Financial Interests, Personal, Advisory Role: Tempus; Financial Interests, Personal, Advisory Role: Zelluna; Financial Interests, Personal, Principal Investigator: Arcus; Financial Interests, Personal, Principal Investigator: Aduro; Financial Interests, Personal, Principal Investigator: Akeso; Financial Interests, Personal, Principal Investigator: Amgen; Financial Interests, Personal, Principal Investigator: Bioatla; Financial Interests, Personal, Principal Investigator: BMS; Financial Interests, Personal, Principal Investigator: CytomX; Financial Interests, Personal, Principal Investigator: Exelixis; Financial Interests, Personal, Principal Investigator: Roche Genentech; Financial Interests, Personal, Principal Investigator: GSK; Financial Interests, Personal, Principal Investigator: Immunicore; Financial Interests, Personal, Principal Investigator: Idera; Financial Interests, Personal, Principal Investigator: Incyte; Financial Interests, Personal, Principal Investigator: Iovance; Financial Interests, Personal, Principal Investigator: Merck, Moderna; Financial Interests, Personal, Principal Investigator: Merck, Serono, Nextcure; Financial Interests, Personal, Principal Investigator: Novartis, Pfizer; Financial Interests, Personal, Principal Investigator: Sanofi/Regeneron; Financial Interests, Personal, Principal Investigator: SeaGen, Torque; Financial Interests, Personal, Principal Investigator: Zelluna; Financial Interests, Institutional, Research Grant: Arcus; Financial Interests, Institutional, Funding: Adura; Financial Interests, Institutional, Funding: Akeso; Financial Interests, Institutional, Funding: Amgen; Financial Interests, Institutional, Funding: Bioatla; Financial Interests, Institutional, Funding: BMS; Financial Interests, Institutional, Funding: CytomX; Financial Interests, Institutional, Funding: Exelixis; Financial Interests, Institutional, Funding: Roche Genentech; Financial Interests, Institutional, Funding: GSK; Financial Interests, Institutional, Funding: Immunicore; Financial Interests, Institutional, Funding: Idera; Financial Interests, Institutional, Funding: Incyte; Financial Interests, Institutional, Funding: Iovance; Financial Interests, Institutional, Funding: Merck, Moderna; Financial Interests, Institutional, Funding: Merck-Serona, Nextcure; Financial Interests, Institutional, Funding: Novartis, Pfizer; Financial Interests, Institutional, Funding: Sanofi/Regeneron; Financial Interests, Institutional, Funding: SeaGen, Torque; Financial Interests, Institutional, Funding: Zelluna. Y. Du: Financial Interests, Personal, Full or part-time Employment, Stocks: Alkermes. M. Desai: Financial Interests, Personal, Full or part-time Employment, Stocks, Patent: Alkermes. Y. Wang: Financial Interests, Personal, Full or part-time Employment, Stocks: Alkermes. L. Sun: Financial Interests, Personal, Full or part-time Employment, Stocks: Alkermes. J. Rege: Financial Interests, Personal, Full or part-time Employment, Stocks: Alkermes. M.R. Middleton: Financial Interests, Personal, Advisory Board: Alkermes; Financial Interests, Personal, Advisory Board: Kineta; Financial Interests, Personal, Advisory Board: Silicon Therapeutics; Financial Interests, Personal, Advisory Board: Immunocore; Financial Interests, Personal, Advisory Board: BMS; Financial Interests, Personal, Advisory Board: Replimune; Financial Interests, Institutional, Funding: Alkerms; Financial Interests, Institutional, Funding: BMS; Financial Interests, Institutional, Funding: Replimune; Financial Interests, Institutional, Funding: GSK; Financial Interests, Institutional, Funding: Merck; Financial Interests, Institutional, Funding: MSD; Financial Interests, Institutional, Funding: Pfizer; Financial Interests, Institutional, Funding: Regeneron; Financial Interests, Institutional, Funding: Bioline; Financial Interests, Institutional, Funding: Immunocore; Financial Interests, Institutional, Funding: Novartis; Financial Interests, Institutional, Funding: Roche; Financial Interests, Institutional, Funding: Medivir; Financial Interests, Institutional, Funding: GenesisCare; Financial Interests, Institutional, Funding: GRAIL. All other authors have declared no conflicts of interest.

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Investigational immunotherapy

976P - The 30-day mortality rate after first cycle of immunotherapy

Presentation Number
976P
Speakers
  • Osman Sutcuoglu (Ankara, Turkey)

Abstract

Background

The aim of this study is to determine the causes of death in patients who received at least one dose of immunotherapy and died within 30 days after the first dose of immunotherapy regardless of the purpose of treatment and cancer type. The second aim of the study is to evaluate the characteristics of the disease and patients before starting immunotherapy and to determine the prophylactic features to be taken to reduce the complications of immunotherapy.

Methods

The data of a total of 1432 patients treated with immunotherapy in six tertiary referral hospital were retrospectively analyzed.

Results

It was determined that 34 (2%) of the patients died within 30 days following the first dose of immunotherapy. Approximately half of the patients (55%) had good performance at the beginning of immunotherapy (ECOG 0-1), again half of the patients had no comorbidity. Death occurred in all patients who received palliative therapy, and most patients (88%) received immunotherapy as second or subsequent line of therapy. The most common diagnosis of death patients were malignant melanoma (40%), lung cancer (24%) and renal cell carcinoma (20%) and other (16%). Twenty-three patients died in the hospital, the most common cause of death was disease progression and thromboembolic events (Table).

Information on death occurred in the first 30 days after immunotherapy

All patients
N=34 (%)
Median time from immunotherapy to death (min-max) (days) 26 (2-30)
Immunotherapy-related immune side effect
Autoimmune nephritis 2 (6%)
Autoimmune hepatitis 1 (3%)
Myocarditis 1 (3%)
Adrenal insufficiency 1 (3%)
Myastenia gravis 1 (3%)
None 28 (82%)
Hyperprogression
Yes 3 (10%)
No 31 (90%)
Death place
Hospital 23 (66%)
Home 9 (28%)
Nursing home 2 (6%)
Cause of death
Disease progression 7 (40%)
Sepsis 5 (15%)
Pulmonary embolism 4 (12%)
Immune side effect 3 (9%)
Myocardial infarction 3 (9%)
Gastrointestinal system bleeding 1 (3%)
Unknown 11 (32%)

Conclusions

The relationship between first 30-day mortality and disease progression/thromboembolic events has been demonstrated in patients using immunotherapy in the treatment of metastatic cancer.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

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Investigational immunotherapy

1019P - Selection of the optimal dose for ALX148, a CD47 blocker, using pharmacokinetic/pharmacodynamic modeling

Presentation Number
1019P
Speakers
  • Oleg Demin Jr (Edinburgh, United Kingdom)

Abstract

Background

ALX148 is a promising CD47 blocking agent currently undergoing clinical trials. Optimal dose selection can be guided by the assessment of target receptor occupancy (RO) and pharmacodynamics (PD) effect in the site of action. While direct measurement of actual RO in the tumor tissues is challenging, mechanistic pharmacokinetic (PK) RO and PD modelling can provide valuable information that can be extrapolated to the clinic. The aims of this study were: (1) to develop mechanistic PK/RO model for ALX148 capable to predict target RO in the tumor tissues and periphery of cancer patients; (2) to estimate PD effect of ALX148 on of phagocytosis; (3) to determine optimal dosage regimes for ALX148.

Methods

A semi-mechanistic PK/RO/PD model was developed. PK of ALX148 and its distribution to the tumor tissues (lymph nodes, spleen and bone marrow) were described in the model. The model includes non-linear clearance of ALX148 due to target CD47 receptor binding and further internalization of the complex. CD47 RO was described on red blood cells and tumor cells taking into account the amount of cells and CD47 expression (molecules per cell). Parameters were fitted against clinical PK and in vitro data. Clinical data on CD47 RO in the periphery was used for model validation.

Results

The model successfully described ALX148 clinical PK and RO data. Predicted trough CD47 RO in spleen, lymph nodes and bone marrow were similar and median value was about 98% (range: 94%-100%) during the treatment with 10 mg/kg QW of ALX148. Further dose escalation didn’t significantly increase CD47 RO. Phagocytosis of cancer cells was predicted to be increased by ∼1.8 times (range: 1-3 times) during the treatment with both regimens of ALX148: 10 mg/kg and 30 mg/kg QW. Dose 3 mg/kg resulted in the lower induction of phagocytosis than 10 mg/kg: 1.6 vs 1.8 (p-value <0.001).

Conclusions

Developed model predicted that 10 mg/kg QW is an optimal dose of ALX148 to occupy more than 90% of CD47 in the tumor tissues to achieve maximal induction of phagocytosis. This approach can be applied for the optimal dose selection of other anti-CD47 agents taking into account their specific features as binding properties, size, etc.

Legal entity responsible for the study

InSysBio.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

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Investigational immunotherapy

975P - Impact of body mass index on the efficacy of immune checkpoint inhibitors in cancer

Presentation Number
975P
Speakers
  • Alejandro Rios Hoyo (Barcelona, Spain)

Abstract

Background

Anti-PD-1/PD-L1 agents have revolutionized the treatment of advanced cancer. However, many patients still do not benefit from these treatments. We sought to evaluate the impact of body mass index on the efficacy of anti-PD-1/PD-L1 drugs.

Methods

Retrospective data was collected from patients with advanced NSCLC (non-small cell lung cancer), genitourinary cancers, or malignant melanoma who received immune checkpoint inhibitor (ICI) treatment with anti-PD-1 or anti-PD-L1. Parameters evaluated included stage, ECOG Performance Status (PS) at initiation of ICI, development of immune related adverse events (irAE), and body mass index (BMI). Univariate and multivariate analyses were performed to assess the association between these parameters and overall survival (OS). The latter was calculated since the first administration of ICI.

Results

One hundred fourteen patients were included in this study. The most frequent tumor origin was lung (70.2%), followed by genitourinary (22.8%) and melanoma (7%). 84.4% of the patients received treatment with an anti-PD-1 agent, whereas 15.5% received treatment with an anti-PD-L1 agent. Patients with a BMI greater than 25 kg/m2 represented 49.2% of the cases. According to BMI classification, patients with underweight, normal-weight, and equal to or greater than overweight, had a median OS of 3.73 months (m), 15.76m, and 19.60m respectively (global p value of <0.001). Statistical analysis revealed that for every unit of increase in BMI, risk of death was reduced by 6%. PS, stage, and BMI remained independently associated with outcome in the multivariate analysis (Table).

Multivariate analysis for overall survival

Variables HR (95% CI) p-value
ECOG PS 2 6.63 (2.56 – 17.21) <0.001
Advanced stage at baseline 1.85 (1 - 3.41) <0.049
Overweight and obesity (BMI >25) 0.21 (0.07 – 0.59) 0.003

Conclusions

Our results suggest that low BMI is associated with worse outcome in patients with advanced cancer treated with ICIs. Upfront nutritional assessment and measures might improve the results of treatments with ICI.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

E. Arriola: Other, Institutional, Invited Speaker: BMS; Other, Institutional, Invited Speaker: AstraZeneca; Other, Institutional, Invited Speaker: Roche; Other, Institutional, Invited Speaker: MSD; Other, Institutional, Invited Speaker: Pfizer; Other, Institutional, Invited Speaker: Lilly; Other, Institutional, Invited Speaker: Boehriger Ingelheim. All other authors have declared no conflicts of interest.

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Investigational immunotherapy

1035TiP - A phase I/Ib trial study of MPT-0118 as monotherapy and in combination with pembrolizumab in subjects with advanced or metastatic solid tumors

Presentation Number
1035TiP
Speakers
  • David Sommerhalder (San Antonio, United States of America)

Abstract

Background

MPT-0118 is an inhibitor of mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) protease developed by Monopteros Therapeutics for the treatment of solid tumors. Despite the transforming effects of immune checkpoint therapy (ICT), objective response rates are still low in solid tumors. In the tumor microenvironment (TME), regulatory T-cells (Treg) are unstable and can be reprogrammed to lose their immunosuppressive function and secrete interferon-γ, offering a strategy to sensitize unresponsive tumors to ICT. Blockade of MALT1 protease by MPT-0118 induces Treg reprogramming in the TME without affecting Treg in healthy tissue, which allows for cytotoxic T-lymphocyte-mediated tumor lysis and recruitment of new tumor-infiltrating lymphocytes. The increased inflammation caused by these effects then increases programmed death-ligand 1 expression allowing synergy between MPT-0118 and pembrolizumab.

Trial design

Monopteros Therapeutics is conducting a first-in-human, phase 1/1b open-label, multicenter, dose-escalation, safety, pharmacokinetics, and biomarker study of MPT-0118 as monotherapy and in combination with pembrolizumab in approximately 70 adults with advanced/metastatic refractory solid tumors. The study will be conducted in 3 parts: Part A: MPT-0118 monotherapy with 3+3 dose-escalation Part B: MPT-0118 in combination with standard dose of pembrolizumab with 3+3 dose-escalation Part C: Cohort expansion of MPT-0118 and pembrolizumab combination at the recommended phase 2 dose (RP2D) MPT-0118 will be administered orally twice daily to subjects in each part of the study, and pembrolizumab will be administered intravenously to subjects in Parts B, and C. Subjects will receive treatment in 3- or 4-week cycles and may continue on the study as long as they are tolerating treatment without disease progression. The primary objectives of Parts A and B are to determine the safety and tolerability, maximum tolerated dose, dose limiting toxicities, and RP2D of MPT-0118 as monotherapy and in combination. The primary objectives of Part C are to confirm safety in combination and to evaluate the preliminary anti-tumor activity.

Clinical trial identification

NCT04859777.

Legal entity responsible for the study

Monopteros Therapeutics Inc.

Funding

Monopteros Therapeutics Inc.

Disclosure

E.A. Lim: Financial Interests, Stocks/Shares: Pfizer. A. Pande: Financial Interests, Personal, Advisory Role: Monopteros Therapeutics; Financial Interests, Member of the Board of Directors: Sio Gene Therapie; Financial Interests, Member of the Board of Directors: Karuna Therapeutics; Financial Interests, Member of the Board of Directors: Immunovant; Financial Interests, Member of the Board of Directors: Autifony Therapeutics; Financial Interests, Member of the Board of Directors: Perception Neurosciences; Financial Interests, Advisory Role: MAPS Public Benefit Corporation; Financial Interests, Advisory Role: MMS Holdings; Financial Interests, Advisory Role: Datavant; Financial Interests, Advisory Role: PureTech Health; Financial Interests, Advisory Role: Avanir Pharmaceuticals. P. Keller: Financial Interests, Personal, Full or part-time Employment: Monopteros Therapeutics; Financial Interests, Personal, Leadership Role: Divide and Conquer. All other authors have declared no conflicts of interest.

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Investigational immunotherapy

1025TiP - SOLTI-1904: Efficacy of spartalizumab across multiple cancer-types in patients with PD1-high mRNA expressing tumors defined by a single and pre-specified cutoff (ACROPOLI)

Presentation Number
1025TiP
Speakers
  • Aleix Prat (Barcelona, Spain)

Abstract

Background

The immune checkpoint inhibitors against programmed death 1 (PD1) or its ligand (PD-L1) has demonstrated significant efficacy in multiple cancer types. Thus, selecting patients most likely to respond to these therapies is necessary. PD-L1 expression by immunohistochemistry has been proposed as a potential predictive biomarker of response. A statistically significant difference in Overall Response Rate (ORR) between PD-L1 positive and PD-L1 negative tumors has been reported. However, there is not a common reference standard for PD-L1 quantification. Moreover, some studies showed efficacy of anti PD1/PD-L1 independently of PD-L1 expression. Recently, association between PD1 mRNA levels and response to anti-PD1 monotherapy across several cancer types has been validated both in silico datasets and in clinical samples, being the 80th percentile of PD1 expressing tumors (PD1-high) strongly correlated with ORR (Pare. Ann Oncol. 2019). We hypothesize that anti-PD1 monotherapy is effective across multiple cancer-types in patients with high mRNA PD1-expressing tumors.

Trial design

ACROPOLI is an open-label, single-arm, non-randomized, phase II study to evaluate the efficacy of the anti-PD-1 spartalizumab in monotherapy in patients with advanced solid PD1-high-expressing tumors (31 different cancer types). Patients could have received any number of previous lines other than immune checkpoint inhibitors. Patients with high levels of PD1 mRNA (Cohort 1; N= 111), as defined by the pre-specified cutoff, will be enrolled in the study. A cohort of 30 patients with PD1-low tumors where the efficacy of PD1 inhibitors in monotherapy has been previously established will also be recruited (Cohort 2). Patients will receive spartalizumab 400 mg/4 weeks. Primary objective is to determine ORR in the PD1-high population. Secondary objectives include other measures of clinical efficacy both in Cohort-1 and 2 (ORR, Clinical Benefit Rate, Progression-Free Survival, Duration of Response, Overall Survival) and evaluation of safety and tolerability. No formal comparison will be performed between two cohorts. Recruitment (10 sites in Spain) started in May 2021.

Clinical trial identification

NCT04802876.

Legal entity responsible for the study

SOLTI.

Funding

Novartis.

Disclosure

A. Prat: Financial Interests, Personal, Invited Speaker: Roche; Financial Interests, Personal, Invited Speaker: Pfizer; Financial Interests, Personal, Invited Speaker: Novartis; Financial Interests, Personal, Invited Speaker: Amgen; Financial Interests, Personal, Invited Speaker: BMS; Financial Interests, Personal, Invited Speaker: Nanostring Technologies; Financial Interests, Personal, Invited Speaker: Daiichi Sankyo; Financial Interests, Personal, Advisory Role: Roche; Financial Interests, Personal, Advisory Role: Pfizer; Financial Interests, Personal, Advisory Role: Novartis; Financial Interests, Personal, Advisory Role: Amgen; Financial Interests, Personal, Advisory Role: BMS; Financial Interests, Personal, Advisory Role: Puma; Financial Interests, Personal, Advisory Role: Oncolytics Biotech; Financial Interests, Personal, Advisory Role: MSD; Financial Interests, Personal, Advisory Role: Guardant Health; Financial Interests, Personal, Advisory Role: Peptomyc; Financial Interests, Personal, Advisory Role: Lilly; Financial Interests, Personal, Leadership Role: Reveal Genomics, SL; Financial Interests, Institutional, Research Grant: Boehringer Ingelheim; Financial Interests, Institutional, Research Grant: Novartis; Financial Interests, Institutional, Research Grant: Roche; Financial Interests, Institutional, Research Grant: Nanostring; Financial Interests, Institutional, Research Grant: Sysmex Europa GmbH; Financial Interests, Institutional, Research Grant: Medica Scientia inno. Research, SL; Financial Interests, Institutional, Research Grant: Celgene; Financial Interests, Institutional, Research Grant: Astellas; Financial Interests, Institutional, Research Grant: Pzifer; Financial Interests, Institutional, Other, Lecture Fees: Nanostring technologies; Financial Interests, Institutional, Other, Clinical Trials: Boehringer Ingelheim; Financial Interests, Institutional, Other, Clinical Trials: Lilly; Financial Interests, Institutional, Other, Clinical Trials: Roche; Financial Interests, Institutional, Other, Clinical Trials: Novartis; Financial Interests, Institutional, Other, Clinical Trials: Amgen; Financial Interests, Institutional, Other, Clinical Trials: Daiichi Sankyo; Financial Interests, Personal, Leadership Role: Beast International Group (BIG); Financial Interests, Personal, Leadership Role: SOLTI Cooperative Group; Financial Interests, Personal, Other, Patronage Committee: SOLTI Foundation; Financial Interests, Personal, Other, Patronage Committee: Actitud Frente al Cáncer Foundation. E. Felip: Financial Interests, Personal, Advisory Board: Amgen; Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Personal, Advisory Board: Bayer; Financial Interests, Personal, Advisory Board: Beigene; Financial Interests, Personal, Advisory Board: Boehringer Ingelheim; Financial Interests, Personal, Advisory Board: Bristol-Myers Squibb; Financial Interests, Personal, Advisory Board: Eli Lilly; Financial Interests, Personal, Advisory Board: F. Hoffman-La Roche; Financial Interests, Personal, Advisory Board: Glaxo Smith Kline; Financial Interests, Personal, Advisory Board: Janssen; Financial Interests, Personal, Advisory Board: Medical Trends; Financial Interests, Personal, Advisory Board: Merck Sharp & Dohme; Financial Interests, Personal, Advisory Board: Merck Serono; Financial Interests, Personal, Advisory Board: Peptomyc; Financial Interests, Personal, Advisory Board: Pfizer; Financial Interests, Personal, Advisory Board: Puma; Financial Interests, Personal, Advisory Board: Regeneron; Financial Interests, Personal, Advisory Board: Sanofi; Financial Interests, Personal, Advisory Board: Syneos Health; Financial Interests, Personal, Advisory Board: Takeda; Financial Interests, Personal, Speaker’s Bureau: Amgen; Financial Interests, Personal, Speaker’s Bureau: AstraZeneca; Financial Interests, Personal, Speaker’s Bureau: Bristol-Myers Squibb; Financial Interests, Personal, Speaker’s Bureau: Eli Lilly; Financial Interests, Personal, Speaker’s Bureau: F. Hoffmann-La Roche; Financial Interests, Personal, Speaker’s Bureau: Janssen; Financial Interests, Personal, Speaker’s Bureau: Medscape; Financial Interests, Personal, Speaker’s Bureau: Merck Sharp & Dohme; Financial Interests, Personal, Speaker’s Bureau: Merck Serono; Financial Interests, Personal, Speaker’s Bureau: Peervoice; Financial Interests, Personal, Speaker’s Bureau: Pfizer; Financial Interests, Personal, Speaker’s Bureau: Springer; Financial Interests, Personal, Speaker’s Bureau: Touch Medical; Financial Interests, Personal, Other, Independent Member Of The Board: Grifols; Financial Interests, Personal, Other, Research Funding to Institution: Fundación Merck Salud. A.M. Arance Fernandez: Financial Interests, Personal, Other, Consultant: Pierre Fabre; Financial Interests, Personal, Advisory Board: Pierre Fabre; Financial Interests, Personal, Other, Travel, Accommodations, Expenses: Pierre Fabre; Financial Interests, Institutional, Funding: Pierre Fabre; Financial Interests, Personal, Other, Consultant: Novartis; Financial Interests, Personal, Advisory Board: Novartis; Financial Interests, Personal, Other, Travel Accommodations, Expenses: Novartis; Financial Interests, Institutional, Funding: Novartis; Financial Interests, Personal, Invited Speaker, Consultant: Roche; Financial Interests, Personal, Speaker’s Bureau: Roche; Financial Interests, Personal, Other, Travel Accommodations, Expenses: Roche; Financial Interests, Institutional, Funding: Roche; Financial Interests, Personal, Other, Consultant: BMS; Financial Interests, Personal, Advisory Board: BMS; Financial Interests, Personal, Other, Travel Accommodations, Expenses: BMS; Financial Interests, Institutional, Funding: BMS; Financial Interests, Personal, Other, Consultant: MSD; Financial Interests, Personal, Advisory Board: MSD; Financial Interests, Personal, Other, Travel Accommodations, Expenses: MSD; Financial Interests, Institutional, Funding: MSD; Financial Interests, Personal, Other, Consultant: Merck; Financial Interests, Personal, Advisory Board: Merck; Financial Interests, Personal, Other, Travel Accommodations, Expenses: Merck; Financial Interests, Institutional, Funding: Merck; Financial Interests, Personal, Other, Consultant: Sanofi; Financial Interests, Personal, Advisory Board: Sanofi; Financial Interests, Personal, Other, Travel Accommodations, Expenses: Sanofi; Financial Interests, Institutional, Funding: Sanofi; Financial Interests, Institutional, Funding: Amgem. J. Martin-Liberal: Financial Interests, Personal, Invited Speaker: Astellas; Financial Interests, Personal, Invited Speaker: Bristol-Myers Squibb; Financial Interests, Personal, Invited Speaker: MSD; Financial Interests, Personal, Invited Speaker: Novartis; Financial Interests, Personal, Invited Speaker: Pierre Fabre; Financial Interests, Personal, Invited Speaker: Pfizer; Financial Interests, Personal, Invited Speaker: Roche; Financial Interests, Personal, Invited Speaker: Sanofi; Financial Interests, Personal, Advisory Board: Bristol-Myers Squibb; Financial Interests, Personal, Advisory Board: Novartis; Financial Interests, Personal, Advisory Board: Pierre Fabre; Financial Interests, Personal, Advisory Board: Roche; Financial Interests, Personal, Advisory Board: Sanofi; Financial Interests, Personal, Research Grant: Sanofi; Financial Interests, Personal, Other, Travel Accommodations, Expenses: Bristol-Myers Squibb; Financial Interests, Personal, Other, Travel: MSD; Financial Interests, Personal, Other, Travel: Novartis; Financial Interests, Personal, Other, Travel: Pierre Fabre; Financial Interests, Personal, Other, Travel: Pfizer; Financial Interests, Personal, Other, Travel: Roche; Financial Interests, Personal, Other, Travel: Ipsen. J. Gavilá: Financial Interests, Institutional, Research Grant: Novartis; Financial Interests, Personal, Other: Novartis; Financial Interests, Institutional, Research Grant: Pfizer; Financial Interests, Personal, Other: Pfizer; Financial Interests, Institutional, Research Grant: Roche; Financial Interests, Personal, Other: Roche. C. Saura Manich: Financial Interests, Personal, Other, Consultant: AstraZeneca; Financial Interests, Personal, Other, Consultant: Daiichi Sankyo; Financial Interests, Personal, Other, Consultant: Eisai; Financial Interests, Personal, Other, Consultant: Exact Sciences; Financial Interests, Personal, Other, Consultant: Exeter Pharma; Financial Interests, Personal, Other, Consultant: F. Hoffmann - La Roche Ltd; Financial Interests, Personal, Other, Consultant: MediTech; Financial Interests, Personal, Other, Consultant: Merck Sharp & Dohme; Financial Interests, Personal, Other, Consultant: Novartis; Financial Interests, Personal, Other, Consultant: Pfizer; Financial Interests, Personal, Other, Consultant: Philips; Financial Interests, Personal, Other, Consultant: Pierre Fabre; Financial Interests, Personal, Other, Consultant: Puma; Financial Interests, Personal, Other, Consultant: Sanofi; Financial Interests, Personal, Other, Consultant: Aventis; Financial Interests, Personal, Other, Consultant: SeaGen; Financial Interests, Personal, Other, Consultant: Zymeworks; Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Personal, Advisory Board: Daiichi Sankyo; Financial Interests, Personal, Advisory Board: Eisai; Financial Interests, Personal, Advisory Board: Exact Sciences; Financial Interests, Personal, Advisory Board: Exeter Pharma; Financial Interests, Personal, Advisory Board: F. Hoffmann - La Roche Ltd; Financial Interests, Personal, Advisory Board: MediTech; Financial Interests, Personal, Advisory Board: Merck Sharp & Dohme; Financial Interests, Personal, Advisory Board: Novartis; Financial Interests, Personal, Advisory Board: Pfizer; Financial Interests, Personal, Advisory Board: Philips; Financial Interests, Personal, Advisory Board: Pierre Fabre; Financial Interests, Personal, Advisory Board: Puma; Financial Interests, Personal, Advisory Board: Sanofi; Financial Interests, Personal, Advisory Board: Aventis; Financial Interests, Personal, Advisory Board: SeaGen; Financial Interests, Personal, Advisory Board: Zymeworks; Financial Interests, Personal, Other, Travel Grants: AstraZeneca; Financial Interests, Personal, Other, Travel Grants: Daiichi Sankyo; Financial Interests, Personal, Other, Travel Grants: Eisai; Financial Interests, Personal, Other, Travel Grants: Exact Sciences; Financial Interests, Personal, Other, Travel Grants: Exeter Pharma; Financial Interests, Personal, Other, Travel Grants: F. Hoffmann - La Roche Ltd; Financial Interests, Personal, Other, Travel Grants: MediTech; Financial Interests, Personal, Other, Travel Grants: Merck Sharp & Dohme; Financial Interests, Personal, Other, Travel Grants: Novartis; Financial Interests, Personal, Other, Travel Grants: Pfizer; Financial Interests, Personal, Other, Travel Grants: Philips; Financial Interests, Personal, Other, Travel Grants: Pierre Fabre; Financial Interests, Personal, Other, Travel Grants: Puma; Financial Interests, Personal, Other, Travel Grants: Sanofi; Financial Interests, Personal, Other, Travel Grants: Aventis; Financial Interests, Personal, Other, Travel Grants: SeaGen; Financial Interests, Personal, Other, Travel Grants: Zymeworks; Financial Interests, Institutional, Other: AstraZeneca; Financial Interests, Institutional, Other: Daiichi Sankyo; Financial Interests, Institutional, Other: Eli Lilly and Company; Financial Interests, Institutional, Other: Genentech; Financial Interests, Institutional, Other: Immunomedics; Financial Interests, Institutional, Other: Macrogenics; Financial Interests, Institutional, Other: Merck Sharp and Dhome España S.A; Financial Interests, Institutional, Other: Novartis; Financial Interests, Institutional, Other: Pfizer; Financial Interests, Institutional, Other: Piqur Therapeutics; Financial Interests, Institutional, Other: Puma; Financial Interests, Institutional, Other: Roche; Financial Interests, Institutional, Other: Synthon; Financial Interests, Institutional, Other: Zenith Pharma. J. Tabernero: Financial Interests, Personal, Other, Consultant: Array Biopharma; Financial Interests, Personal, Invited Speaker, Consultant: AstraZeneca; Financial Interests, Personal, Invited Speaker, Consultant: Avvinity; Financial Interests, Personal, Invited Speaker, Consultant: Bayer; Financial Interests, Personal, Invited Speaker, Consultant: Boehringer Ingelheim; Financial Interests, Personal, Invited Speaker, Consultant: Chugai; Financial Interests, Personal, Invited Speaker, Consultant: Daiichi Sankyo; Financial Interests, Personal, Invited Speaker, Consultant: F. Hoffmann La Roche Ltd; Financial Interests, Personal, Invited Speaker, Consultant: Genentech Inc; Financial Interests, Personal, Invited Speaker, Consultant: HalioDX SAS; Financial Interests, Personal, Invited Speaker, Consultant: Hutchison MediPharma International; Financial Interests, Personal, Invited Speaker, Consultant: Ikena Oncology; Financial Interests, Personal, Invited Speaker, Consultant: IQVIA; Financial Interests, Personal, Invited Speaker, Consultant: Lilly; Financial Interests, Personal, Invited Speaker, Consultant: Menarini; Financial Interests, Personal, Invited Speaker, Consultant: Merck Serono; Financial Interests, Personal, Invited Speaker, Consultant: Merus; Financial Interests, Personal, Invited Speaker, Consultant: MSD; Financial Interests, Personal, Invited Speaker, Consultant: Mirati; Financial Interests, Personal, Invited Speaker, Consultant: Neophore; Financial Interests, Personal, Invited Speaker, Consultant: Novartis; Financial Interests, Personal, Invited Speaker, Consultant: Orion Biotechnology; Financial Interests, Personal, Invited Speaker, Consultant: Peptomyc; Financial Interests, Personal, Invited Speaker, Consultant: Pfizer; Financial Interests, Personal, Invited Speaker, Consultant: Pierre Fabre; Financial Interests, Personal, Invited Speaker, Consultant: Samsung Bioepis; Financial Interests, Personal, Invited Speaker, Consultant: Sanofi; Financial Interests, Personal, Invited Speaker, Consultant: Seattle Genetics; Financial Interests, Personal, Invited Speaker, Consultant: Servier; Financial Interests, Personal, Invited Speaker, Consultant: Taiho; Financial Interests, Personal, Invited Speaker, Consultant: Tessa Therapeutics; Financial Interests, Personal, Invited Speaker, Consultant: TheraMyc; Financial Interests, Personal, Expert Testimony: Imedex; Financial Interests, Personal, Expert Testimony: Medscape Education; Financial Interests, Personal, Expert Testimony: MJH Life Sciences; Financial Interests, Personal, Expert Testimony: PeerView Institute for Medical Education; Financial Interests, Personal, Expert Testimony: Physicians Education Resource (PER). All other authors have declared no conflicts of interest.

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Investigational immunotherapy

1028TiP - ARC-12: Phase I/Ib dose escalation and dose expansion study to evaluate the safety and tolerability of AB308 + zimberelimab (AB122) in advanced malignancies

Presentation Number
1028TiP
Speakers
  • Justin A. Call (San Antonio, United States of America)

Abstract

Background

PD-(L)1 inhibitors provide durable clinical benefit for some patients with various tumors; however, combination immune therapy may be needed to optimize outcomes. T-cell Immunoglobulin and ITIM domain (TIGIT), expressed on activated T and natural killer (NK) cells, inhibits antitumor immunity upon binding CD155 on tumors. AB308, an anti-TIGIT humanized IgG1 monoclonal antibody (mAb) with functional FcR binding, reverses TIGITCD155-mediated T-cell inhibition in preclinical models. ARC-12 will assess if AB308-mediated TIGIT pathway blockade augments zimberelimab (zim; anti-PD-1 mAb) activity.

Trial design

This is a first-in-human, open-label study of AB308 + zim in pts with advanced malignancies. For the dose-escalation, pts must have solid tumors without a standard-of-care therapy or relapsed/refractory (R/R) NHL; ≥1 measurable lesion; and ECOG performance score 0-1. AB308 + zim will be given intravenously (IV) once every 3 weeks (Q3W; Part A) or 4 weeks (Q4W; Part B; Table). In Part A, Cohort 1 will follow 3+3+6 rules and allow AB308 dose adjustment if dose-limiting toxicities (DLTs) warrant; all other dose-escalation cohorts will use 3+3 rules. Upon Cohort 2 DLT period completion, Part B will begin enrollment independently and in parallel to Part A. A recommended dose for expansion (RDE) for AB308 + zim may be identified for both Q3W and Q4W schedules. In the dose-expansion, disease-specific cohorts will be enrolled (Table); all pts in each cohort will receive AB308 + zim at either Q3W or Q4W. For both the dose-escalation and dose-expansion, the primary endpoints assess safety and tolerability of AB308 + zim; secondary endpoints include pharmacokinetics, immunogenicity, and objective response rate for AB308 + zim. Additional secondary endpoints in the dose-expansion are disease control rate and duration of response. ARC-12 is actively recruiting in the USA (NCT04772989).

Dose-Escalation and Dose-Expansion are both section headers and should match in format/style please

Dose-Escalation
Part A, Cohorts 1–3 3 escalating doses of AB308 IV Q3W +360 mg zim IV Q3W
Part B, Cohorts 4–6 3 escalating doses of AB308 IV Q4W +480 mg zim IV Q4W
Dose-Expansion
Cohort 1: 1L PD-L1-high non-small cell lung cancer (TPS ≥50%) AB308 + zim combo RDE IV Q3W or Q4W
Cohort 2: 2L+ R/R melanoma;PD-(L)1-experienced
Cohort 3: 2L+ gastric/gastroesophageal junction (CPS ≥1) or esophageal cancer (CPS ≥10)
Cohort 4: 2L+ cervical cancer (CPS ≥1)
Cohort 5: 3L+ R/R diffuse large B-cell lymphoma or 4L+ R/R multiple myeloma

Clinical trial identification

NCT04772989.

Editorial acknowledgement

Medical writing assistance was provided by Amanda Martin, PhD, of Medical Expressions (Chicago, IL) and was funded by Arcus Biosciences.

Legal entity responsible for the study

Arcus Biosciences, Inc.

Funding

Arcus Biosciences, Inc.

Disclosure

M.A. Mckean: Financial Interests, Institutional, Research Grant: Acentage Pharma Group; Financial Interests, Institutional, Research Grant: Bicycle Therapeutics; Financial Interests, Institutional, Research Grant: Dragonfly Therapeutics; Financial Interests, Institutional, Research Grant: Epizyme; Financial Interests, Institutional, Research Grant: Exelixis; Financial Interests, Institutional, Research Grant: Genentech; Financial Interests, Institutional, Research Grant: GlaxoSmithKline; Financial Interests, Institutional, Research Grant: IDEAYA Biosciences; Financial Interests, Institutional, Research Grant: Ikena Oncology; Financial Interests, Institutional, Research Grant: Infinity Pharmaceuticals; Financial Interests, Institutional, Research Grant: Jacobio Pharmaceuticals; Financial Interests, Institutional, Research Grant: Moderna; Financial Interests, Institutional, Research Grant: NBE Therapeutics; Financial Interests, Institutional, Research Grant: Novartis; Financial Interests, Institutional, Research Grant: Oncorus; Financial Interests, Institutional, Research Grant: Plexxikon; Financial Interests, Institutional, Research Grant: Prelude Therapeutics; Financial Interests, Institutional, Research Grant: Regeneron Pharmaceuticals; Financial Interests, Institutional, Research Grant: Sapience Therapeutics; Financial Interests, Institutional, Research Grant: Seattle Genetics; Financial Interests, Institutional, Research Grant: Tizona Therapeutics; Financial Interests, Institutional, Research Grant: Tmunity Therapeutics; Financial Interests, Institutional, Research Grant: TopAlliance Biosciences; Financial Interests, Institutional, Advisory Role: Array BioPharma; Financial Interests, Institutional, Advisory Role: AstraZeneca; Financial Interests, Institutional, Advisory Role: MedPage Today; Financial Interests, Institutional, Advisory Role: Pfizer; Financial Interests, Institutional, Advisory Role: Regeneron Pharmaceuticals. P. Foster: Financial Interests, Personal, Full or part-time Employment: Arcus; Financial Interests, Personal, Stocks/Shares: Arcus. C. Trudeau: Financial Interests, Personal, Full or part-time Employment: Arcus; Financial Interests, Personal, Stocks/Shares: Arcus. M. Scharville: Financial Interests, Personal, Full or part-time Employment: Arcus; Financial Interests, Personal, Stocks/Shares: Arcus. A. El-Baghdady: Financial Interests, Personal, Full or part-time Employment: Arcus; Financial Interests, Personal, Stocks/Shares: Arcus. A. Patnaik: Financial Interests, Personal, Other, Honoraria: Texas Society of Clinical Oncology; Financial Interests, Personal, Advisory Role: Novartis; Financial Interests, Personal, Advisory Role: Merck; Financial Interests, Personal, Advisory Role: Seattle Genetics; Financial Interests, Personal, Advisory Role: Silverback Therapeutics; Financial Interests, Personal, Advisory Role: Bayer; Financial Interests, Institutional, Research Grant: Pfizer; Financial Interests, Institutional, Research Grant: Livzon; Financial Interests, Institutional, Research Grant: Klus Pharma; Financial Interests, Institutional, Research Grant: Fochon Pharmaceuticals; Financial Interests, Institutional, Research Grant: Plexxikon; Financial Interests, Institutional, Research Grant: Corvus Pharmaceuticals; Financial Interests, Institutional, Research Grant: Five Prime Therapeutics; Financial Interests, Institutional, Research Grant: Infinity Pharmaceuticals; Financial Interests, Institutional, Research Grant: Ionova; Financial Interests, Institutional, Research Grant: Lilly; Financial Interests, Institutional, Research Grant: Daiichi Sankyo; Financial Interests, Institutional, Research Grant: Surface Oncology; Financial Interests, Institutional, Research Grant: Upsher-Smith; Financial Interests, Institutional, Research Grant: Arcus Ventures; Financial Interests, Institutional, Research Grant: Exelixis; Financial Interests, Institutional, Research Grant: AbbVie; Financial Interests, Institutional, Research Grant: Astellas Pharma; Financial Interests, Institutional, Research Grant: Symphpgen; Financial Interests, Institutional, Research Grant: Sanofi; Financial Interests, Institutional, Research Grant: Merck; Financial Interests, Institutional, Research Grant: Tesaro; Financial Interests, Institutional, Research Grant: Forty Seven; Financial Interests, Institutional, Research Grant: Bolt Biotherapeutics; Financial Interests, Institutional, Research Grant: Pieris Pharmaceuticals; Financial Interests, Institutional, Research Grant: Vigeo Therapeutics; Financial Interests, Institutional, Research Grant: Syndax; Financial Interests, Institutional, Research Grant: Seattle Genetics. All other authors have declared no conflicts of interest.

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Investigational immunotherapy

980P - Phase Ib study of a liposomal formulation of eribulin (E7389-LF) + nivolumab (Nivo) in patients (pts) with advanced solid tumors

Presentation Number
980P
Speakers
  • Noboru Yamamoto (Chuo-ku, Japan)

Abstract

Background

Eribulin is a halichondrin-class microtubule dynamics inhibitor with cytotoxic and vascular remodeling effects leading to tumor immune modulation. E7389-LF is a liposomal formulation of eribulin designed to enhance antitumor activity and improve pharmacokinetic (PK) profiles. The combination of E7389-LF + Nivo is expected to show antitumor activity by cytotoxic and antitumor immune effects.

Methods

The primary objective of this phase 1b study (Study 120) was to determine the recommended phase 2 dose (RP2D). Nivo was administered IV at 360 mg Q3W (day 1 of a 21-day cycle) and 240 mg Q2W (days 1 and 15 of a 28-day cycle) in combination with E7389-LF (1.7–2.1 mg/m2 Q3W and 1.1–1.4 mg/m2 Q2W, respectively; Table) to pts with advanced solid tumors for which no alternative standard or effective therapy existed.

Results

Of the 25 enrolled pts, 16 were male, median age was 55 years (range 34–79), and 21 had ECOG PS 0. A dose-limiting toxicity (DLT) was observed in 3 pts (Table), and all DLTs were resolved. Based on neutrophil counts, Q3W dosing was preferred. Safety profiles in all cohorts were determined to be tolerable. The most common grade ≥ 3 treatment-related adverse events were neutropenia (52%), leukopenia (36%), and lymphopenia (16%). A partial response was observed in 4 pts (16%; Table). There were no substantial changes in the PK profiles of E7389-LF and Nivo compared to those of each monotherapy. In all cohorts, plasma-vasculature-related markers and interferon-related markers tended to increase from baseline during cycle 1. Of the 9 pts evaluable for pre/post biopsy and who had an immune-desert or immune-excluded phenotype at baseline, 4 had an immune-inflamed phenotype at C2D1.

Conclusions

E7389-LF + Nivo was tolerable in pts with advanced solid tumors, with antitumor effects and positive effects on vascularity and antitumor immunity. Based on these results, the RP2D was determined to be E7389-LF 2.1 mg/m2 Q3W + Nivo 360 mg Q3W.

Dosing, DLTs, responses

Schedule E7389-LF dose Nivo dose n DLTs Grade and type Partial response by RECIST v1.1 n (tumor type)
Once every 2 weeks (Q2W) 1.1 mg/m2 240 mg 7 Dose skip of E7389-LF on D15 due to absolute neutrophil count <1000/mm3 1 (intrahepatic cholangiocarcinoma)
1.4 mg/m2 6 Grade 3 febrile neutropenia 0
Once every 3 weeks (Q3W) 1.7 mg/m2 360 mg 6 Grade 3 febrile neutropenia 2 (thymic carcinoma)
2.1 mg/m2 6 None 1 (small cell lung cancer)

Clinical trial identification

NCT04078295.

Editorial acknowledgement

Medical writing support was provided by Heather A. Mitchell, PhD, of Oxford PharmaGenesis Inc., Newtown, PA, USA, and was funded by Eisai Inc., Woodcliff Lake, NJ, USA.

Legal entity responsible for the study

Eisai Co. Ltd., Tokyo, Japan

Funding

Study funding from Eisai Co. Ltd., Tokyo, Japan. Nivolumab provided by Ono Pharmaceutical Co. Ltd., Osaka, Japan.

Disclosure

N. Yamamoto: Financial Interests, Personal, Invited Speaker: AstraZeneca; Financial Interests, Personal, Advisory Board: Boehringer Ingelheim; Financial Interests, Personal, Advisory Board: Chugai; Financial Interests, Personal, Invited Speaker: Chugai; Financial Interests, Personal, Advisory Board: Cimic; Financial Interests, Personal, Invited Speaker: Daiichi-Sankyo; Financial Interests, Personal, Advisory Board: Eisai; Financial Interests, Personal, Invited Speaker: Eli Lilly; Financial Interests, Personal, Invited Speaker: ONO; Financial Interests, Personal, Advisory Board: Otsuka; Financial Interests, Personal, Invited Speaker: Pfizer; Financial Interests, Personal, Invited Speaker: Sysmex; Financial Interests, Personal, Advisory Board: Takeda; Financial Interests, Institutional, Principal Investigator: AbbVie; Financial Interests, Institutional, Principal Investigator: Astellas; Financial Interests, Institutional, Principal Investigator: Bayer; Financial Interests, Institutional, Principal Investigator: BMS; Financial Interests, Institutional, Principal Investigator: Boehringer Ingelheim; Financial Interests, Institutional, Principal Investigator: Chiome Bioscience; Financial Interests, Institutional, Principal Investigator: Chugai; Financial Interests, Institutional, Principal Investigator: Daiichi-Sankyo; Financial Interests, Institutional, Principal Investigator: Eisai; Financial Interests, Institutional, Principal Investigator: Eli Lilly; Financial Interests, Institutional, Principal Investigator: GSK; Financial Interests, Institutional, Principal Investigator: Janssen Pharma; Financial Interests, Institutional, Principal Investigator: Kyowa-Hakko Kirin; Financial Interests, Institutional, Principal Investigator: Merck; Financial Interests, Institutional, Principal Investigator: MSD; Financial Interests, Institutional, Principal Investigator: Novartis; Financial Interests, Institutional, Principal Investigator: ONO; Financial Interests, Institutional, Principal Investigator: Otsuka; Financial Interests, Institutional, Principal Investigator: Pfizer; Financial Interests, Institutional, Principal Investigator: Sumitomo Dainippon; Financial Interests, Institutional, Principal Investigator: Taiho; Financial Interests, Institutional, Principal Investigator: Takeda. T. Shimizu: Financial Interests, Personal, Speaker’s Bureau: AbbVie; Financial Interests, Personal, Speaker’s Bureau: Daiichi-Sankyo; Financial Interests, Personal, Speaker’s Bureau: Eisai; Financial Interests, Personal, Speaker’s Bureau: Takeda Oncology; Financial Interests, Personal, Speaker’s Bureau: MSD; Financial Interests, Personal, Advisory Board: Daiichi-Sankyo; Financial Interests, Personal, Advisory Board: AbbVie; Financial Interests, Personal, Advisory Board: Takeda Oncology; Financial Interests, Institutional, Research Grant: Novartis; Financial Interests, Institutional, Research Grant: AbbVie; Financial Interests, Institutional, Research Grant: Daiichi-Sankyo; Financial Interests, Institutional, Research Grant: Takeda Oncology; Financial Interests, Institutional, Research Grant: Eli Lilly; Financial Interests, Institutional, Research Grant: LOXO Oncology; Financial Interests, Institutional, Research Grant: Bristol-Myers Squibb; Financial Interests, Institutional, Research Grant: Eisai; Financial Interests, Institutional, Research Grant: Incyte; Financial Interests, Institutional, Research Grant: AstraZeneca; Financial Interests, Institutional, Research Grant: Pfizer; Financial Interests, Institutional, Research Grant: Chordia Therapeutics; Financial Interests, Institutional, Research Grant: Symbio Pharmaceuticals; Financial Interests, Institutional, Research Grant: 3D-Medicine; Financial Interests, Institutional, Research Grant: Five Prime; Financial Interests, Institutional, Research Grant: PharmaMar; Financial Interests, Institutional, Research Grant: Astellas; Financial Interests, Institutional, Principal Investigator: Novartis; Financial Interests, Institutional, Principal Investigator: AbbVie; Financial Interests, Institutional, Principal Investigator: Daiichi-Sankyo; Financial Interests, Institutional, Principal Investigator: Takeda Oncology; Financial Interests, Institutional, Principal Investigator: Eli Lilly; Financial Interests, Institutional, Principal Investigator: LOXO Oncology; Financial Interests, Institutional, Principal Investigator: Bristol-Myers Squibb; Financial Interests, Institutional, Principal Investigator: Eisai; Financial Interests, Institutional, Principal Investigator: Incyte; Financial Interests, Institutional, Principal Investigator: AstraZeneca; Financial Interests, Institutional, Principal Investigator: Pfizer; Financial Interests, Institutional, Principal Investigator: Chordia Therapeutics; Financial Interests, Institutional, Principal Investigator: Symbio Pharmaceuticals; Financial Interests, Institutional, Principal Investigator: 3D-Medicine; Financial Interests, Institutional, Principal Investigator: Five Prime; Financial Interests, Institutional, Principal Investigator: PharmaMar; Financial Interests, Institutional, Principal Investigator: Astellas. Y. Nakamura: Financial Interests, Institutional, Research Grant: Genomedia; Financial Interests, Institutional, Research Grant: Guardant Health; Financial Interests, Institutional, Research Grant: Chugai Pharma; Financial Interests, Institutional, Research Grant: Taiho Pharma; Financial Interests, Institutional, Research Grant: Daiichi-Sankyo Pharma. M. Nishino: Financial Interests, Personal, Speaker’s Bureau: AstraZeneca; Financial Interests, Personal, Speaker’s Bureau: Bristol-Myers Squibb; Financial Interests, Personal, Speaker’s Bureau: Boehringer Ingelheim Japan; Financial Interests, Personal, Speaker’s Bureau: Chugai; Financial Interests, Personal, Speaker’s Bureau: Eli Lilly Japan; Financial Interests, Personal, Speaker’s Bureau: MSD; Financial Interests, Personal, Speaker’s Bureau: ONO Pharmaceutical; Financial Interests, Personal, Speaker’s Bureau: Pfizer Japan; Financial Interests, Personal, Speaker’s Bureau: Taiho. T. Koyama: Financial Interests, Personal, Speaker’s Bureau: Sysmex; Financial Interests, Personal, Speaker’s Bureau: Chugai; Financial Interests, Personal, Principal Investigator: PACT. S. Iwasa: Financial Interests, Personal, Speaker’s Bureau: ONO; Financial Interests, Personal, Speaker’s Bureau: BMS; Financial Interests, Institutional, Research Grant: Eisai; Financial Interests, Institutional, Research Grant: ONO; Financial Interests, Institutional, Research Grant: BMS. K. Sudo: Financial Interests, Personal, Invited Speaker: Eisai Co. Ltd.; Financial Interests, Personal, Sponsor/Funding: Eisai Co. Ltd. K. Yonemori: Financial Interests, Personal, Invited Speaker: Eisai; Financial Interests, Personal, Advisory Board: Eisai. S. Shiono: Financial Interests, Personal, Full or part-time Employment: Ono Pharmaceutical Co. Ltd. T. Suzuki: Financial Interests, Personal, Full or part-time Employment: Eisai Co. Ltd. T. Takase: Financial Interests, Personal, Full or part-time Employment: Eisai Co. Ltd. S. Takashima: Financial Interests, Personal, Full or part-time Employment: Eisai. K. Yamaguchi: Financial Interests, Personal, Full or part-time Employment: Eisai Co. Ltd. T. Semba: Financial Interests, Personal, Full or part-time Employment: Eisai Co. Ltd. K. Shitara: Financial Interests, Personal, Invited Speaker: AbbVie; Financial Interests, Personal, Advisory Board: AbbVie; Financial Interests, Personal, Advisory Board: Amgen; Financial Interests, Personal, Advisory Board: Astellas; Financial Interests, Personal, Advisory Board: Boehringer Ingelheim; Financial Interests, Personal, Advisory Board: Bristol-Myers Squibb; Financial Interests, Personal, Advisory Board: Daiichi Sankyo; Financial Interests, Personal, Advisory Board: GlaxoSmithKline; Financial Interests, Personal, Advisory Board: Lilly; Financial Interests, Personal, Advisory Board: MSD; Financial Interests, Personal, Invited Speaker: Novartis; Financial Interests, Personal, Advisory Board: Novartis; Financial Interests, Personal, Advisory Board: ONO Pharmaceutical; Financial Interests, Personal, Advisory Board: Pfizer; Financial Interests, Personal, Advisory Board: Taiho Pharmaceutical; Financial Interests, Personal, Advisory Board: Takeda; Financial Interests, Personal, Invited Speaker: Yakult Honsha; Financial Interests, Institutional, Research Grant: Astellas; Financial Interests, Institutional, Research Grant: Chugai Pharmaceutical; Financial Interests, Institutional, Research Grant: Daiichi Sankyo; Financial Interests, Institutional, Research Grant: Eisai; Financial Interests, Institutional, Research Grant: Lilly; Financial Interests, Institutional, Research Grant: Medi Science; Financial Interests, Institutional, Research Grant: MSD; Financial Interests, Institutional, Research Grant: Ono Pharmaceutical; Financial Interests, Institutional, Research Grant: Sumitomo Dainippon; Financial Interests, Institutional, Research Grant: Taiho Pharmaceutical. All other authors have declared no conflicts of interest.

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Investigational immunotherapy

995P - A pan-cancer analysis of KMT2D as a potential biomarker for immune checkpoint therapy

Presentation Number
995P
Speakers
  • Xiaoqian Guan (Guangzhou, China)

Abstract

Background

Lysine methyltransferase 2D (KMT2D), which encodes a histone H3 lysine 4 methyltransferase, is one of the most frequently mutated genes in cancer patients. Previous studies showed that KMT2D-mutant tumor cell lines exhibited increasing immune infiltration and KMT2D mutation was correlated with higher tumor mutation burden (TMB) in multiple types of human cancers in TCGA datasets, suggesting that KMT2D-deficient tumors might be more sensitive to immune checkpoint inhibitors (ICIs), but the correlation of KMT2D mutation status with immune response in clinical remains unknown.

Methods

Next generation sequencing (NGS) data of 10336 pan-cancer patients were obtained from the MSK-IMPACT Clinical Sequencing cohort (MSKCC, NAT Med 2017). NGS data and clinical data of 1661 pan-cancer patients (MSKCC, NAT Genet 2019) treated with ICIs were analyzed to explore the association between KMT2D gene alteration and TMB. Moreover, the association between KMT2D alteration and therapeutic efficacy of ICIs was explored in the MSKCC-2019 cohort.

Results

A total of 9% (1087/11997) of the pan-cancer patients in all cohorts carried KMT2D alteration, and the highest alteration frequency cancer types were mature B-cell neoplasms (51/134, 38.06%), skin cancer (non-Melanoma, 42/149, 28.19%) and bladder cancer (178/638, 27.9%), respectively. The commonly variant types of KMT2D were non-structural variants. In MSKCC-2019 cohort treatment with ICIs, the TMB level of KMT2D-altered group was significantly higher than wild group (P<0.01) and the overall survival (OS) of KMT2D-altered group were significantly longer than wild group (OS, median, 27.00 vs 15.00 months; HR=0.7675 [95%CI: 0.6249-0.9426], P=0.0189). However, in the MSKCC-2017 cohort without immunotherapy, the OS of the KMT2D-altered group was significantly shorter than wild group (OS, median, 22.22 vs 26.36 months; HR=1.202 [95%CI: 1.039-1.391], P=0.0075), suggesting KMT2D might be an immunotherapy efficacy predictive factor but not a prognostic factor.

Conclusions

The results indicated that KMT2D gene alteration was associated with a higher TMB level in pan-cancer patients, and patients carrying KMT2D alteration might easily benefit from ICIs.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

X. Zhong: Financial Interests, Personal and Institutional, Member: 3DMed. Inc. T. Chen: Financial Interests, Personal and Institutional, Member: 3DMed. Inc. M. Huang: Financial Interests, Personal and Institutional, Member: 3DMed. Inc. All other authors have declared no conflicts of interest.

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