Background

Immune-checkpoint inhibitors (ICIs) are characterised by durable responses and improved survival in patients with advanced non-small cell lung cancer (NSCLC). Unfortunately, only certain patients can benefit from immunotherapy, therefore a feasible tool is urgently needed to predict the patients who might benefit from ICIs in clinical practice.

Methods

We enrolled 76 patients with advanced NSCLC and treated them with ICIs in three independent cohorts. Using transcriptome data analysis of a training set (n=35), we constructed a predictive signature consisting of immune-related gene pairs (IRGPs). The predictive signature was first validated in the testing set (n=20) and then validated in an independent cohort containing 19 patients recruited from the Cancer Hospital/Institute, Chinese Academy of Medical Sciences (CICAMS).

Results

Based on a gene expression profile from the GSE93157 database, we proposed the IRGP index (IRGPI): four IRGPs were significantly associated with progression-free survival (PFS) of patients with NSCLC treated with ICIs. We then validated the IRGPI using a test set and its prognostic performance was further verified at various protein levels in an additional independent set. Stratification and multivariate Cox regression analyses revealed that IRGPI was an independent prognostic predictor. Notably, IRGPI exhibited more powerful predictive performance than PD-L1. Further analysis revealed that the IRGPI-low and PD-L1-high subgroups showed the best response to anti-PD-1 immunotherapy.

Conclusions

Our study highlights the potential predictive value of IRGPI for responses of ICIs in advanced NSCLC. This signature may be a powerful prognostic tool and help further optimise the use of ICIs.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

Background

There are multiple first-line treatment options in the management of metastatic renal cell carcinoma (mRCC). In the face of this broad treatment landscape, a reliable predictive biomarker of response to immune checkpoint-based therapy (ICBT) remains a critical unmet need. We sought to evaluate plasma exosome microRNAs (miRNAs) for such a role.

Methods

Eleven miRNAs that are over-expressed in RCC and/or immune-associated were evaluated in 40 patients with mRCC (prior to initiating ICBT) and 30 healthy volunteers. Exosomes were extracted from 500 uL of plasma and used for miRNAs extraction. MiRNAs expression was evaluated by RT-PCR. Cycle threshold values were normalized to miR-30-3b, and the relative quantity of the expression (RQ) was compared to healthy volunteers and calculated using the 2^ΔΔCt method. Mann-Whitney U test was used to evaluate the expression of miRNAs between mRCC patients and healthy volunteers and according to response to first line ICBT between responders (defined as radiographic complete response, partial response or stable disease; n=27) v non-responders (defined as radiographically progressive disease; n=13). The cut-off value of significant miRNAs expression was established by Youden’s index.

Results

Higher expression of miRNA-1233-3p (median 1.85 v 0.81, p=0.008) and miR155-3p [miR-155] (3.69 v 0.21, p=0.006) were found in patients compared to healthy volunteers. Amongst patients, miR-155 was expressed at a significantly lower level in responders than non-responders (median 0.61 v 35.29, p=0.042). Disease control rate amongst patients with low expression of miR-155 (RQ ≤ 2.5) was 84.2%, and 52.4% amongst those with high expression (RQ ≥ 2.5) (p=0.032).

Conclusions

Lower expression of miR-155 was associated with better response to ICBT. Functionally, miR-155 is involved in modulation of the tumour microenvironment and diversification of antibody repertoire. Evaluation of miR-155 biological and molecular mechanisms in TME and immune response modulation is currently ongoing.

Legal entity responsible for the study

The authors.

Funding

This research was supported by the GUMOC Bayer Research Grant Program jointly established by the Genitourinary Medical Oncologists of Canada (GUMOC) and Bayer Canada; Canadian Urological Association Scholarship Foundation (CUASF) and the Canadian Urological Association in collaboration with Kidney Cancer Research Network of Canada (KCRNC.

Disclosure

M. Soleimani: Financial Interests, Personal, Invited Speaker, honorarium: Pfizer Canada; Financial Interests, Institutional, Research Grant: Abbvie Pharmaceuticals; Financial Interests, Institutional, Research Grant: Astellas. D.J. Khalaf: Financial Interests, Personal, Advisory Role, consulting fees: Janssen. B.J. Eigl: Financial Interests, Personal, Other, honorarium: Pfizer Canada; Financial Interests, Personal, Other, honorarium: Janssen; Financial Interests, Personal, Other, honorarium: AstraZeneca; Financial Interests, Personal, Other, honorarium: Merck; Financial Interests, Personal, Other, honorarium: Roche; Financial Interests, Personal, Other, honorarium: Bayer. K.N. Chi: Financial Interests, Personal and Institutional, Research Grant, and personal fees: Janssen; Financial Interests, Personal and Institutional, Research Grant, and personal fees: Astellas; Financial Interests, Personal and Institutional, Research Grant, and personal fees: Sanofi; Financial Interests, Personal and Institutional, Research Grant, and personal fees: AstraZeneca; Financial Interests, Personal and Institutional, Research Grant, and personal fees: Bayer; Financial Interests, Personal and Institutional, Research Grant, and personal fees: Pfizer; Financial Interests, Personal and Institutional, Research Grant, and personal fees: Roche. C.K. Kollmannsberger: Financial Interests, Personal, Other, honorarium: Pfizer Canada; Financial Interests, Personal, Other, honorarium: Astellas; Financial Interests, Personal, Other, honorarium: Janssen; Financial Interests, Personal, Other, honorarium: Merck; Financial Interests, Personal, Other, honorarium: Ipsen; Financial Interests, Personal, Other, honorarium: Bristol-Meyers Squibb; Financial Interests, Personal, Advisory Board: Pfizer; Financial Interests, Personal, Advisory Board: Astellas; Financial Interests, Personal, Advisory Board: Janssen; Financial Interests, Personal, Advisory Board: Merck; Financial Interests, Personal, Advisory Board: Eisai; Financial Interests, Personal, Advisory Board: Ipsen; Financial Interests, Personal, Advisory Board: EMD Serono; Financial Interests, Personal, Advisory Board: Bristol-Myers Squibb; Financial Interests, Personal, Other, honorarium: Eisai. L. Nappi: Financial Interests, Personal, Other, honorarium: Ipsen Biopharmaceuticals Inc; Financial Interests, Personal, Other, honorarium: Bayer Healthcare Pharmaceuticals. All other authors have declared no conflicts of interest.

Background

Comprehensive genomic profiling tests are approved for refractory cancer patients in Japan with the condition that all tests be annotated by a molecular tumor board (MTB), at 12 core and 33 hub government-designated hospitals. Our study assessing the MTB performance of all core hospitals using 50 simulated cases indicated that sharing information on available matched therapies, particularly for genomic alterations with low evidence levels by the Japanese classification (PMID: 33249514), is needed to improve the quality of recommendations by MTBs (Kage H, et al #1097 ESMO 2021). Based on these results, we initiated the Japanese Society of Medical Oncology/Health Authority of the Japanese Government cooperative virtual educational program for Improving clinical annotation.

Trial design

Eligibility included each MTB at hub hospitals or individual medical oncologists at core hospitals and they had to complete the clinical annotation of all 50 simulated cases. The 50 simulated cases were randomly divided into 2 groups (n=25 each) by a central biostatistician based on concordance between the consensus annotation and the MTB annotations at the core hospitals. After submitting the treatment recommendations of the first 25 cases, the participants will learn the consensus annotation of these cases at a workshop; they will then submit the treatment recommendations of the next 25 cases. The primary endpoint is the frequency of participants who meet the acceptance criteria at post-workshop study: 90% and 40% concordance with the consensus annotation for genomic alterations with high and low evidence levels, respectively. The threshold acceptance rate is assumed to be 20%, and the planned sample size is > 24 participants. Secondary endpoints include improvements in the concordance rates of the pre- and post-workshop studies at each hospital and the concordance rate of each evidence level. A study evaluating the clinical annotation using artificial intelligence is also underway. The recruitment of participants has started, and the workshop is scheduled for July 18, 2021.

Legal entity responsible for the study

The authors.

Funding

Japanese Ministry of Health, Labour and Welfare.

Disclosure

K. Sunami: Financial Interests, Personal, Speaker’s Bureau: Chugai; Financial Interests, Personal, Speaker’s Bureau: Pfizer; Financial Interests, Personal, Speaker’s Bureau: Novartis; Financial Interests, Personal, Speaker’s Bureau: Sysmex; Financial Interests, Personal, Speaker’s Bureau: Amgen . Y. Naito: Financial Interests, Personal, Speaker’s Bureau: AstraZeneca; Financial Interests, Personal, Speaker’s Bureau: Bayer; Financial Interests, Personal, Speaker’s Bureau: Chugai; Financial Interests, Personal, Speaker’s Bureau: Eisai; Financial Interests, Personal, Speaker’s Bureau: Eli Lilly; Financial Interests, Personal, Speaker’s Bureau: Fuji Film Toyama Chemistry; Financial Interests, Personal, Speaker’s Bureau: Gardant; Financial Interests, Personal, Speaker’s Bureau: Nihon Kayaku; Financial Interests, Personal, Speaker’s Bureau: Novartis; Financial Interests, Personal, Speaker’s Bureau: Ono; Financial Interests, Personal, Speaker’s Bureau: Pfizer; Financial Interests, Personal, Speaker’s Bureau: Taiho; Financial Interests, Personal, Speaker’s Bureau: Takeda; Financial Interests, Personal, Research Grant: ABBVIE; Financial Interests, Personal, Research Grant: Boehringer Ingelheim; Financial Interests, Personal, Research Grant: Chugai; Financial Interests, Personal, Research Grant: Daiichi Sankyo; Financial Interests, Personal, Research Grant: Ono; Financial Interests, Personal, Research Grant: Pfizer; Financial Interests, Personal, Research Grant: Roche; Financial Interests, Personal, Research Grant: Taiho. D. Ennishi: Financial Interests, Institutional, Other, Honoraria : Eisai Pharmaceutical Co., Ltd.; Financial Interests, Institutional, Other, Honoraria: Kyowa Kirin Pharmaceutical Co., Ltd.; Financial Interests, Institutional, Research Grant: Chugai Pharmaceutical Co., Ltd.; Financial Interests, Institutional, Research Grant: Nipponshinyaku Pharmaceutical Co., Ltd.. H. Kage: Financial Interests, Institutional, Research Grant: Konica Minolta, Inc.. M. Kanai: Financial Interests, Personal, Other, Honoraria : Chugai Pharmaceutical Co., Ltd. H. Kenmotsu: Financial Interests, Personal, Other, Honoraria : Chugai Pharmaceutical Co, Ltd.; Financial Interests, Personal, Other, Honoraria : Ono Pharmaceutical Co, Ltd; Financial Interests, Personal, Other, Honoraria: Boeringer Ingelheim; Financial Interests, Personal, Other, Honoraria: Eli Lilly K.K; Financial Interests, Personal, Other, Honoraria: Kyowa Hakko Kirin Co., Ltd; Financial Interests, Personal, Other, Honoraria: Bristol-Myers Squibb; Financial Interests, Personal, Other, Honoraria: MSD; Financial Interests, Personal, Other, Honoraria: Novartis Pharma K.K; Financial Interests, Personal, Other, Honoraria: Daiichi-Sankyo Co., Ltd; Financial Interests, Personal, Other, Honoraria: AstraZeneca K.K; Financial Interests, Personal, Other, Honoraria: Pfizer; Financial Interests, Personal, Other, Honoraria: Taiho Pharma; Financial Interests, Institutional, Research Grant: Chugai Pharmaceutical Co, Ltd.; Financial Interests, Institutional, Research Grant: Novartis Pharma K.K.; Financial Interests, Institutional, Research Grant: Daiichi-Sankyo Co., Ltd; Financial Interests, Institutional, Research Grant: AstraZeneca K.K.. T. Koyama: Financial Interests, Personal, Other, Honoraria : Chugai; Financial Interests, Personal, Other, Honoraria : Sysmex; Financial Interests, Personal, Research Grant: PACT. D. Sakai: Financial Interests, Personal, Speaker’s Bureau: Chugai Pharma; Financial Interests, Institutional, Research Grant: Chugai Pharma; Financial Interests, Institutional, Research Grant: Lilly Japan; Financial Interests, Institutional, Research Grant: Chugai Pharma; Financial Interests, Institutional, Research Grant: Yakult Honsha; Financial Interests, Institutional, Research Grant: Ono Pharmaceutical; Financial Interests, Institutional, Research Grant: Astellas Pharma; Financial Interests, Institutional, Research Grant: Incyte; Financial Interests, Institutional, Research Grant: Taiho Pharmaceutical; Financial Interests, Institutional, Research Grant: Eisai. K. Ichiro: Financial Interests, Personal, Other, Honoraria : Pfizer Inc.; Financial Interests, Personal, Other, Honoraria : Chugai Pharmaceutical Co.; Financial Interests, Personal, Other, Honoraria : Bayer Pharmaceutical Co.; Financial Interests, Personal, Other, Honoraria : AstraZeneca Inc.. T. Kozuki: Financial Interests, Personal, Other, Honoraria : AstraZeneca; Financial Interests, Personal, Other, Honoraria : Eli-Lilly Japan; Financial Interests, Personal, Other, Honoraria : Taiho Pharmaceutical Co.; Financial Interests, Personal, Other, Honoraria : Chugai Pharmaceutical Co.; Financial Interests, Personal, Other, Honoraria : MSD; Financial Interests, Personal, Other, Honoraria : Bristol-Myers Squibb; Financial Interests, Personal, Other, Honoraria : Ono Pharmaceutical Co.; Financial Interests, Personal, Other, Honoraria : Pfizer Japan; Financial Interests, Personal, Other, Honoraria : Nippon Boehringer Ingelheim; Financial Interests, Personal, Other, Honoraria : Merck Biopharma; Financial Interests, Personal, Other, Honoraria : Nippon Kayaku; Financial Interests, Personal, Other, Honoraria: Novartis; Financial Interests, Personal, Other, Honoraria: Daiichi-Sankyo; Financial Interests, Personal, Other, Honoraria: Kyowa Hakko Kirin; Financial Interests, Institutional, Research Grant: Chugai Pharmaeutical Co.; Financial Interests, Institutional, Research Grant: AstraZeneca; Financial Interests, Institutional, Research Grant: Eli Lilly Japan; Financial Interests, Institutional, Research Grant: Taiho Pharmaceutical Co.; Financial Interests, Institutional, Research Grant: Bristl-Myers Squibb; Financial Interests, Institutional, Research Grant: MSD; Financial Interests, Institutional, Research Grant: Kyowa Hakko Kirin; Financial Interests, Institutional, Research Grant: Merck Biopharma. H. Sakashita: Financial Interests, Personal, Other, Honoraria : CHUGAI PHARMACEUTICAL CO.; Financial Interests, Personal, Other, Honoraria : TAIHO PHARMACEUTICAL CO.; Financial Interests, Personal, Other, Honoraria : DAIICHI SANKYO CO.; Financial Interests, Personal, Other, Honoraria : AstraZeneca; Financial Interests, Personal, Other, Honoraria : Nippon Boehringer Ingelheim CO.; Financial Interests, Personal, Other, Honoraria : ONO PHARMACEUTICAL CO.; Financial Interests, Personal, Other, Honoraria : Bristol Myers Squibb; Financial Interests, Personal, Other, Honoraria : MSD; Financial Interests, Institutional, Research Grant: SBI PHARMACEUTICAL CO; Financial Interests, Institutional, Research Grant: TAIHO PHARMACEUTICAL CO.; Financial Interests, Institutional, Research Grant: Pfizer Japan Inc.; Financial Interests, Institutional, Research Grant: MSD; Financial Interests, Institutional, Research Grant: Nippon Boehringer Ingelheim CO.; Financial Interests, Institutional, Research Grant: Novartis; Financial Interests, Institutional, Research Grant: CHUGAI PHARMACEUTICAL CO.; Financial Interests, Institutional, Research Grant: AstraZeneca; Financial Interests, Institutional, Research Grant: Nihon Servier. S. Kohsaka: Financial Interests, Institutional, Research Grant: AstraZeneca; Financial Interests, Institutional, Research Grant: Boehringer Ingelheim; Financial Interests, Institutional, Research Grant: Eisai; Financial Interests, Institutional, Research Grant: Daiichi Sankyo; Financial Interests, Institutional, Research Grant: Chordia Therapeutics. T. Yoshino: Financial Interests, Personal, Other, Honoraria : Taiho; Financial Interests, Personal, Other, Honoraria : Chugai; Financial Interests, Personal, Other, Honoraria : Eli Lilly; Financial Interests, Personal, Other, Honoraria : Merc Biopharma; Financial Interests, Personal, Other, Honoraria : Bayer; Financial Interests, Personal, Other, Honoraria : Ono; Financial Interests, Institutional, Research Grant: Taiho; Financial Interests, Institutional, Research Grant: Sumitomo Dainippon; Financial Interests, Institutional, Research Grant: Ono; Financial Interests, Institutional, Research Grant: Chugai; Financial Interests, Institutional, Research Grant: Amgen; Financial Interests, Institutional, Research Grant: Parexel International; Financial Interests, Institutional, Research Grant: MSD; Financial Interests, Institutional, Research Grant: Daiichi Snakyo; Financial Interests, Institutional, Research Grant: Sanofi. All other authors have declared no conflicts of interest.

Background

Cancer stem cells (CSC) have been suggested as a mechanism of resistance and relapse in BC. TN and HER2+ BC have been associated with a more immunogenic tumor microenvironment, with higher presence of tumor-infiltrating lymphocytes (TILs) and activation of pathways as PD-L1. ALDH1 is a CSC marker that appears to be predictive of clinical outcomes. The study aims to analyze ALDH1 and PD-L1 expression, and the presence of TILs in TN and HER2+ BC tumors, and its association with clinical-pathological characteristics and clinical outcomes.

Methods

Retrospective study of 75 TN and HER2+ BC patients treated with neoadjuvant chemotherapy between 2008 and 2018. Minimum follow-up was 24 months or until death. ALDH1, PD-L1 expression and TILs subtypes were assessed by immunohistochemistry. ALDH1 and PD-L1 were positive if expression ≥1%. TILs were evaluated following International Expert Consensus recommendations with 15 as cut off for high (HTILs) or low (LTILs).

Results

ALDH1 expression was related with HTILs (p=0.005) and PD-L1+ tumors (p=0.004). ALDH1+ tumors present higher CD3+ (p=0.008), CD4+ (p=0.005), CD8+ (p=0.003), CD20+ (p=0.006) TILs. PD-L1+ was related to TILs (p=0.0001). TN/ALDH1+ tumors were related to PD-L1+ (p=0.026), CD20+ (p=0.006) and HTILs (p=0.01). No associations were found in HER2+/ALDH1+ tumors. HER2+/PD-L1+ were related to positive androgen receptor (AR) (p=0.029), HTILs (p < 0.001) and CD20+ (p=0.001). ALDH1+ (p=0.018), PD-L1+ (p=0.004) and HTILs (p < 0.001) were related to smaller tumors. ALDH1+ was related to pathologic complete response (PCR) (p=0.048). HTILs were related to postmenopausal status (p=0.035). Median disease-free survival (DFS) and overall survival had not been reached. HTILs were related with improved DFS (p=0,027). Table: 182P

Clinical-pathological characteristics

Conclusions

ALDH1+ relates to PD-L1+, HITLs, CD3+, CD4+, CD8+, CD20+ and PCR. This could mean that ALDH1+ tumors are more immunogenic. Further investigations are needed to reveal possible therapies in this setting.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

Background

Well-differentiated lung neuroendocrine tumours (NETs), classified as typical (TC) and atypical (AC) carcinoids, are 30% of NETs. Angiogenesis plays an essential role in the development and progression of NETs. In this context, a higher vascular network represents a marker of differentiation, with positive prognostic implications. This phenomenon is called ’neuroendocrine paradox’, with vascularization being inversely related to tumour aggressiveness. No data are available about the role of angiogenesis in left vs right-sided lung NETs.

Methods

We have retrospectively evaluated microvessel density (MD) by immunohistochemical staining for CD34 positive endothelial cells & through hot spot method in peritumoral and intra-tumoral areas, comparing right and left lung parenchyma in 53 lung NETs. We collected patients’ data and analysed them through SPSS system.

Results

Median age was 66 years (39-81), 56.6% males, 26.4% smokers, 24.5% AC, 40.5% left-sided tumours, 69.8% TNM stage I at diagnosis. Mitotic count was <2/10 HPF in 79.2%, absence of necrosis in 71.7%; 39.6% with a Ki67≤2%, 52.8% with a Ki67 of 3-19%. NE markers (synaptophysin, chromogranin A,TTF-1) were positive in 92.5%, 75.5% and 35.8%. Median follow-up was 23 months (0.7-323), 2-years and 5-years PFS rates were 100% and 93.8%, respectively. 2-years and 5-years OS rates were both 96.2%. MD was evaluated in 41 cases, 19 left-sided and 22 right-sided tumours. The median values were higher in right than left parenchyma (MD: 252 vs 195, number of vessels: 759 vs 529, average vessel area 202 vs 182). We detected a statistically significant association between 18 FDG positivity and lower MD (p=0.001) as well as with lower number of vessels (p=0.003).

Conclusions

This study suggests a biological rationale for a different angiogenesis according to primary tumour side in left vs right parenchyma for lung NETs. 18FGD PET positivity (a well-known poor prognostic factor for NETs) correlated with lower vascularization. Left-sided tumours were associated with lower MD, number of vessels and average vessel area, with potential prognostic impact. These data could support NET paradox also in lung parenchyma, paving the way for a more personalized treatment for lung NET.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

Background

In the DESTINY-Breast01 study, T-DXd demonstrated a strong efficacy in HER2+ MBC patients (pts) with and without asymptomatic central nervous system (CNS) metastases. T-DXd has also showed promising antitumor activity in HER2-LE (IHC 1+ or 2+ and lack of HER2 amplification) MBC. DEBBRAH is assessing the efficacy and safety of T-DXd in HER2+ and HER2-LE MBC pts with BM and/or LMC.

Trial design

This is an open-label, single-arm, multicenter, phase 2 study. A total of 39 pts will be assigned to one of the following 5 cohorts: (1) HER2+ MBC with non-progressing BM after radiotherapy and/or surgery (N=8); (2) HER2+ or HER2-LE MBC with asymptomatic untreated BM (N=10); (3) HER2+ MBC with progressing BM after local treatment (N=7); (4) HER2-LE MBC with progressing BM after local treatment (N=7); (5) HER2+ or HER2-LE MBC with LMC (N=7). Main selection criteria include: (a) Pts age ≥18 years with pretreated HER2+ or HER2-LE MBC with stable, progressing, or untreated BM and/or LMC; (b) Cohorts 2–4: measurable brain disease; (c) For HER2+ MBC pts: previous treatment with a taxane and ≥1 HER2-targeted therapy for MBC; (d) For HER2-LE MBC pts who are hormone receptor (HR)-negative: previous treatment with ≥1 chemotherapy regimen for MBC. If HR+: previous treatment with ≥1 chemotherapy and 1 endocrine regimen for MBC. Pts will receive 5.4 mg/kg T-DXd intravenously on day 1 of a 21-day cycle until disease progression, unacceptable toxicity, or consent withdrawal. The primary endpoint for cohort 1 is 16-week progression-free survival as per RANO-BM for CNS lesions and RECIST v.1.1 for extracranial lesions; for cohorts 2–4, CNS overall response rate; for cohort 5, overall survival. Secondary endpoints: additional efficacy outcome and safety as per CTCAE v.5.0. Exploratory endpoints: patient-reported outcomes and predictive or prognostic biomarkers. A single-arm binomial design is used for cohorts 1–4 and a time-to-event design for cohort 5. A futility interim analysis has been planned in cohort 1 after accrual of 4 pts. Sample size was planned to attain an 80% power at nominal level of one-sided α of 0.05 in each cohort.

Clinical trial identification

NCT04420598.

Legal entity responsible for the study

MedSIR.

Funding

AZ/Daiichi Sankyo.

Disclosure

M. Vaz Batista: Non-Financial Interests, Personal, Other, Travel, Accommodations, Expenses: Daiichi Sankyo. J.M. Pérez-Garcia: Financial Interests, Personal, Advisory Role: Roche, Lilly, Daiichi Sankyo; Non-Financial Interests, Personal, Other, Travel, Accommodations, Expenses: Roche. A. Llombart Cussac: Financial Interests, Personal, Project Lead: Eisai, Celgene, Lilly, Pfizer, Roche, Novartis, MSD; Financial Interests, Personal, Stocks/Shares: MedSIR, Initia-Research; Financial Interests, Personal, Advisory Role: Lilly, Roche, Pfizer, Novartis, Pierre-Fabre, GenomicHealth, GSK; Financial Interests, Personal, Speaker’s Bureau: Lilly, AstraZeneca, MSD; Financial Interests, Institutional, Research Grant: Roche, Foundation Medicine, Pierre-Fabre, Agendia; Non-Financial Interests, Personal, Other, Travel, Accommodations, Expenses: Roche, Lilly, Novartis, Pfizer, AstraZeneca. M. Ruiz Borrego: Financial Interests, Personal, Advisory Role: AstraZeneca, Daiichi Sankyo. F. Racca: Financial Interests, Personal, Advisory Role: Bristol Myers Squibb; Financial Interests, Personal, Speaker’s Bureau: Roche, Bristol Myers Squibb; Financial Interests, Personal, Expert Testimony: Pharmore Research, Psyma; Non-Financial Interests, Personal, Other, Travel, Accommodations, Expenses: Roche, Merck Sharp & Dohme, Bristol Myers Squibb. S. Servitja: Financial Interests, Personal, Advisory Role: Daiichi Sankyo, AstraZeneca, MSD, Genomic health; Financial Interests, Personal, Speaker’s Bureau: Roche, MSD, Eisai. L. Lema: Non-Financial Interests, Personal, Other, Travel, Accommodations, Expenses: Pfizer. M. Galàn Garmaje: Financial Interests, Personal, Advisory Role: Novartis; Financial Interests, Personal, Speaker’s Bureau: Eli Lilly, Novartis, Pierre-Fabre, Roche, Bristol Myers Squibb; Non-Financial Interests, Personal, Other, Travel, Accommodations, Expenses: Novartis, Roche, Bristol Myers Squibb. S. González-Santiago: Financial Interests, Personal, Advisory Role: GSK, MSD, Roche, Pfizer. M. Gion: Financial Interests, Personal, Other, honoraria: Roche; Non-Financial Interests, Personal, Other, Travel, Accommodations, Expenses: Pfizer. J. Cortés: Financial Interests, Personal, Advisory Role: Roche, Celgene, Cellestia, AstraZeneca, Biothera Pharmaceutical, Merus, Seattle Genetics, Daiichi Sankyo, Erytech, Athenex, Polyphor, Lilly, Servier, Merck Sharp&Dohme, GSK, Leuko, Bioasis, Clovis Oncology; Financial Interests, Personal, Other, honoraria: Roche, Novartis, Celgene, Eisai, Pfizer, Samsung Bioepis, Lilly, Merck Sharp&Dohme, Daiichi Sankyo; Financial Interests, Institutional, Research Grant: Roche, Ariad pharmaceuticals, AstraZeneca, Baxalta GMBH/Servier Affaires, Bayer healthcare, Eisai, F. Hoffman-La Roche, Guardanth health, Merck Sharp&Dohme, Pfizer, Piqur Therapeutics, Puma C, Queen Mary University of London.; Financial Interests, Personal, Stocks/Shares: MedSIR. S. Braga: Non-Financial Interests, Personal, Other, Travelling, hotel and meal expenses: Daiichi Sankyo; Financial Interests, Personal, Advisory Role: Daiichi Sankyo; Financial Interests, Personal, Other, honoraria: Daiichi Sankyo. All other authors have declared no conflicts of interest.

Background

Tipifarnib is a potent and selective inhibitor of the enzyme farnesyltransferase (FT). While all RAS isoforms (KRAS/NRAS/HRAS) are FT substrates, only HRAS is exclusively dependent upon farnesylation for membrane localization and signaling activation. Oncogenic RAS pathway mutations (NRAS, KRAS, CBL, and PTPN11) are seen in ∼30% of patients (pts) with CMML and are associated with a proliferative phenotype and adverse outcomes. Initial findings suggested tipifarnib may have greater activity in pts with RAS wildtype (wt) CMML. Given these findings, we investigated the activity of tipifarnib in pts with CMML and other MDS/MPN with specific biomarkers of interest.

Methods

This Ph2 study (NCT02807272) is a single-arm, open-label trial investigating the anti-tumor activity of tipifarnib in pts with CMML and MDS/MPN. Pts received tipifarnib 400 mg administered orally twice daily on days 1-21 of 28-day treatment cycles until progression of disease or unacceptable toxicity. The primary objectives were to assess ORR per MDS/MPN IWG criteria in KRAS/NRAS wt and mutant CMML pts and to examine ORR in pts with MDS/MPN with high and low CXCR4/CXCR2 ratio in the bone marrow. Secondary objectives included safety and additional efficacy analyses.

Results

44 pts (37 CMML and 7 MDS/MPN) were treated with tipifarnib. All pts had at least one treatment-related adverse event (AE), and 15 (34%) pts had at least one treatment-related serious AE. Seven (16%) pts discontinued tipifarnib due to treatment-related AEs. There were no treatment-related deaths. The most frequently observed treatment-related AEs (all grades) were anemia, nausea, diarrhea, and fatigue. Thirty-two evaluable CMML pts were had an overall ORR of 21.9% (7/32). ORR was 14.3% (3/21) in KRAS/NRAS wt pts and 33.3% (3/9) in pts with KRAS and/or NRAS mutation; two pts had unknown KRAS/NRAS status. Four MDS/MPN evaluable pts had an ORR of 25%; sample size was too small to meaningfully evaluate CXCR4/CXCR2 ratio in these pts.

Conclusions

Overall, data from this Ph2 trial showed that in general, tipifarnib was reasonably well tolerated and demonstrated modest efficacy in a difficult-to-treat patient population with limited therapeutic options.

Clinical trial identification

NCT02807272.

Legal entity responsible for the study

Kura Oncology.

Funding

Kura Oncology.

Disclosure

M.M. Patnaik: Financial Interests, Personal, Advisory Board: Kura Oncology. M.A. Sekeres: Financial Interests, Personal, Advisory Board: BMS; Financial Interests, Personal, Advisory Board: Takeda; Financial Interests, Personal, Advisory Board: Novartis. A. DeZern: Financial Interests, Personal, Advisory Board: Taiho; Financial Interests, Personal, Advisory Board: Novartis; Financial Interests, Personal, Advisory Board: AbbVie. S. Luger: Financial Interests, Personal, Advisory Role: Daichii-Sankyo; Financial Interests, Personal, Advisory Role: Pfizer; Financial Interests, Personal, Advisory Role: BMS; Financial Interests, Personal, Advisory Role: Acceleron; Financial Interests, Personal, Advisory Role: Agios; Financial Interests, Personal, Advisory Role: Loxo Oncology; Financial Interests, Personal and Institutional, Research Grant: Onconova; Financial Interests, Personal and Institutional, Research Grant: Kura Oncology; Financial Interests, Personal and Institutional, Research Grant: F. Hoffmann-La Roche; Financial Interests, Personal and Institutional, Research Grant: Ariad; Financial Interests, Personal and Institutional, Research Grant: Biosight. R. Bejar: Financial Interests, Personal, Advisory Role: Gilead; Financial Interests, Personal, Advisory Role: BMS; Financial Interests, Personal, Advisory Role: Epizyme; Financial Interests, Personal, Advisory Role: Takeda; Financial Interests, Personal, Advisory Role: AbbVie; Financial Interests, Personal, Advisory Role: Astex; Financial Interests, Personal and Institutional, Research Grant: Takeda; Financial Interests, Personal and Institutional, Research Grant: BMS; Financial Interests, Personal, Stocks/Shares: Aptose Biosciences; Financial Interests, Personal, Full or part-time Employment: Aptose Biociences. G. Hobbs: Financial Interests, Personal and Institutional, Research Grant: Incyte; Financial Interests, Personal and Institutional, Research Grant: Bayer; Financial Interests, Personal and Institutional, Research Grant: Constellation; Financial Interests, Personal, Advisory Board: Incyte; Financial Interests, Personal, Advisory Board: Constellation; Financial Interests, Personal, Advisory Board: AbbVie; Financial Interests, Personal, Advisory Board: Novartis; Financial Interests, Personal, Advisory Board: BMS/Celgene. G.J. Roboz: Financial Interests, Personal, Advisory Role: AbbVie; Financial Interests, Personal, Advisory Role: Agios; Financial Interests, Personal, Advisory Role: Amgen; Financial Interests, Personal, Advisory Role: Amphivena Therapeutics; Financial Interests, Personal, Advisory Role: Astellas Pharma; Financial Interests, Personal, Advisory Role: Astex Pharmaceuticals; Financial Interests, Personal, Advisory Role: AstraZeneca; Financial Interests, Personal, Advisory Role: Array BioPharma/Pfizer; Financial Interests, Personal, Advisory Role: Celator Pharmaceticals; Financial Interests, Personal, Advisory Role: Celgene; Financial Interests, Personal, Advisory Role: Clovis Oncology; Financial Interests, Personal, Advisory Role: CTI BioPharma; Financial Interests, Personal, Advisory Role: Genoptix; Financial Interests, Personal, Advisory Role: Immune Pharmaceuticals; Financial Interests, Personal, Advisory Role: Janssen Pharmaceuticals; Financial Interests, Personal, Advisory Role: Jazz Pharmaceuticals; Financial Interests, Personal, Advisory Role: Orsenix; Financial Interests, Personal, Advisory Role: Juno Therapeutics; Financial Interests, Personal, Advisory Role: MEI Pharma; Financial Interests, Personal, Advisory Role: MedImmune; Financial Interests, Personal, Advisory Role: Novartis; Financial Interests, Personal, Advisory Role: Onconova Therapeutics; Financial Interests, Personal, Advisory Role: Roche/Genetech; Financial Interests, Personal, Advisory Role: Sunesis; Financial Interests, Personal and Institutional, Research Grant: Celletis. M. Leoni, B. Martell: Financial Interests, Personal, Full or part-time Employment: Kura Oncology. E. Padron: Financial Interests, Personal and Institutional, Research Grant: Incyte; Financial Interests, Personal and Institutional, Research Grant: Kura Oncology; Financial Interests, Personal and Institutional, Research Grant: BMS; Financial Interests, Personal, Advisory Role: Stemline; Financial Interests, Personal, Advisory Board: Blueprint; Financial Interests, Personal, Advisory Board: Taiho. All other authors have declared no conflicts of interest.

Background

Clinical application of artificial intelligence in cervical cancer cytology screening is still limited, so a Cervical Cancer Artificial Intelligence Screening System (CAISS) was aimed to established in this study.

Methods

The study consisted of a multicenter population-based study and randomized controlled trial (RCT) performed in China, enrolling 16,056 individuals aged over 18 who had liquid-based cytology pap test with eligible cervical cytological WSIs. 11,468 individuals’ WSIs from Sun Yat-sen Memorial Hospital (SYSMH) were randomly assigned (4:1) into training and internal validation dataset to train CAISS, and validated in SYSMH internal, Guangzhou Women and Children Medical Center (GWCMC), The Third Affiliated Hospital of Guangzhou Medical University (TAHGMU) validation datasets, and SYSMH prospective validation dataset. The RCT was conducted to compare the performance between CAISS, cytotechnicians, and CAISS-assisted. The sensitivity, specificity, accuracy, and AUC were used to assess CAISS's performance.

Results

The sensitivity of CAISS in identifying patients with abnormal cytology grades was 0.906, 0.902, 0.918 in the SYSMH internal, GWCMC external and TAHGMU external validation datasets, respectively. In prospective validation dataset, the CAISS showed similar sensitivity (0.946 vs 0.909, p= 0.304) and AUC (0.947 vs 0.948, p=0.952) to cytotechnician, and CAISS-assisted achieved better sensitivity, than cytotechnician alone (p= 0.024; p= 0.0006). In randomized controlled dataset, the specificity and accuracy of CAISS-assisted were significantly outperformed CAISS (0.989 vs 0.854, p< 0.001; 0.990 vs 0.861, p< 0.001), and no statistical difference in sensitivity between CAISS and cytotechnician (p= 0.552).

Conclusions

In this study, CAISS achieved high sensitivity for diagnosing cervical cytology grade that rivals cytotechnicians’ performance, and help cytotechnicians improve diagnostic sensitivity and accuracy to a higher level, which could improve the effectiveness of cervical cancer screening.

Clinical trial identification

NCT04551287.

Legal entity responsible for the study

Yufang Yu.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

Background

Next-generation targeted therapies for anaplastic lymphoma kinase-positive (ALK+) non-small cell lung cancer are associated with improved clinical outcomes, however, tumors develop resistance thus requiring subsequent therapies. Limited data are available on ALK TKI sequencing. The aim of our study was to understand duration of post-brigatinib ALK TKI therapy in the real-world setting.

Methods

Adults with ≥ 1 claim for brigatinib (index date; ID) between 01-Apr-2017 and 30-Sep-2020 were identified in IQVIA’s Pharmacy Claims Database. Patients had ≥ 12 months of data pre-ID and were followed until the end of available data. Kaplan-Meier methods estimated time to treatment discontinuation (TTD) for brigatinib and the subsequent ALK TKI.

Results

413 brigatinib patients were included (median age: 57.9 years; 58.4% female; median follow-up 8.4 months). Prior to initiating brigatinib, 195 patients had front-line crizotinib with or without subsequent ALK TKIs, 133 had crizotinib followed by alectinib and/or ceritinib, 62 had only crizotinib, 99 had only alectinib, and 80 had no observed ALK TKI. 167 (40.4%) brigatinib patients discontinued or switched to another ALK TKI. Median (95% confidence interval [CI]) brigatinib TTD was 10.3 (8.2-15.0) months. Among patients who discontinued brigatinib, 100 (59.9%) received subsequent ALK-TKIs. Lorlatinib was the most common next ALK TKI (57.0%), followed by brigatinib retreatment (16.0%), alectinib (13.0%), ceritinib (10.0%), and crizotinib (4.0%). The median (95% CI) TTD of the post-brigatinib ALK TKI was 7.2 (3.9-13.8) months. In patients who received crizotinib then brigatinib, the median (95% CI) TTD of the post-brigatinib ALK TKI was 6.7 (3.7-22.2) months. In patients who received lorlatinib after brigatinib was discontinued, median (95% CI) lorlartinib TTD was 8.0 (3.9-not reached) months.

Conclusions

These results indicate that brigatinib has real-world durable clinical effects for patients. Treatment with subsequent TKIs, can still bring benefit to patients after discontinuing brigatinib. More formalized prospective data are needed to establish sequencing recommendations.

Legal entity responsible for the study

IQVIA.

Funding

Takeda.

Disclosure

M.O. Jahanzeb: Financial Interests, Personal and Institutional, Research Grant: Eli Lilly; Financial Interests, Personal and Institutional, Research Grant: Boehringer Ingelheim; Financial Interests, Personal and Institutional, Research Grant: Callisto; Financial Interests, Personal and Institutional, Research Grant: Takeda; Financial Interests, Personal, Invited Speaker: Novartis; Financial Interests, Personal, Invited Speaker: Roche/Genentech; Financial Interests, Personal, Invited Speaker: Pfizer; Financial Interests, Personal, Invited Speaker: Takeda; Financial Interests, Personal, Invited Speaker: Puma; Financial Interests, Personal, Invited Speaker: BMS; Financial Interests, Personal, Invited Speaker: AstraZeneca; Financial Interests, Personal, Invited Speaker: Merck. H.M. Lin: Financial Interests, Personal, Full or part-time Employment: Takeda; Financial Interests, Personal, Stocks/Shares: Takeda. Y. Wu: Financial Interests, Personal, Full or part-time Employment: Takeda; Financial Interests, Personal, Stocks/Shares: Takeda. M. Gorritz: Financial Interests, Personal, Full or part-time Employment: IQVIA. C.B. McGuiness: Financial Interests, Personal, Full or part-time Employment: IQVIA; Financial Interests, Personal, Stocks/Shares: Pfizer. K. Sun: Financial Interests, Personal, Full or part-time Employment: IQVIA. C. Chen: Financial Interests, Institutional, Full or part-time Employment: IQVIA. P. Zhang: Financial Interests, Personal, Full or part-time Employment: Takeda. D.R. Camidge: Financial Interests, Personal, Other, Honoraria: AstraZeneca; Financial Interests, Personal, Other, Honoraria: Takeda; Financial Interests, Personal, Other, Honoraria: Arrys/Kyn; Financial Interests, Personal, Other, Honoraria: Genoptix; Financial Interests, Personal, Other, Honoraria: G1 Therapeutics (DSMB); Financial Interests, Personal, Other, Honoraria: Mersana Therapeutics; Financial Interests, Personal, Other, Honoraria: Roche/Genentech; Financial Interests, Personal, Other, Honoraria: Ignyta; Financial Interests, Personal, Other, Honoraria: Daiichi Sankyo; Financial Interests, Personal, Other, Honoraria: Hansoh SRC; Financial Interests, Personal, Other, Honoraria: Bio-Thera DSMB; Financial Interests, Personal, Other, Honoraria: Lycera; Financial Interests, Personal, Other, Honoraria: Revolution Med; Financial Interests, Personal, Other, Honoraria: Orion; Financial Interests, Personal, Other, Honoraria: Clovis; Financial Interests, Personal, Other, Honoraria: Celgene; Financial Interests, Personal, Other, Honoraria: Novartis; Financial Interests, Personal and Institutional, Research Grant: ARIAD/Takeda.

Background

Despite the increasing number of genes associated with hereditary breast/ovarian cancer (HBOC), BRCA1/2 explain most cases of this entity. Both BRCA1 and BRCA2 contribute to ovarian cancer (OC), cumulative risk of 25-40% and 11-18%, respectively. In contrast to other populations, HBOC Portuguese patients (pts) have a higher prevalence of BRCA2 variants, partially due to the effect of the founder BRCA2 variant: c.156_157insAlu. The aim of this study was to map and analyze BRCA1/2 variants from OC pts in our HBOC program.

Methods

From 502 OC index pts tested between Jan 2000-Dec 2020, 86 were diagnosed with a BRCA1/2 pathogenic variant (PV) (17%). In these HBOC families further 21 OC pts were confirmed as BRCA1/2 carriers. Frequency and spectrum of BRCA1/2 variants were analyzed. Variants were mapped across the gene and the previously described ovarian cancer cluster region (OCCR), for the 107 BRCA1/2 OC pts.

Results

We observed 52 PV in BRCA1 (48.6%) and 55 in BRCA2 (51.4%). The Portuguese BRCA2 founder variant c.156_157insAlu was the most frequent event (16/55: 29.1%), almost 3 times the most frequent BRCA1 variant: c.5266dup (6/52: 11.5%). Although BRCA1 and BRCA2 prevalence were rather similar, copy number variations (CNVs) had a higher contribution for BRCA1 (10/52: 19.2%) than for BRCA2 (3/55: 5.5%). Mapping revealed that exon 11 of BRCA2 harbored 32.7% of all variants while BRCA1 exon 10 included 55.8% of PVs in this gene. While 46.2% of BRCA1 variants (29/52) fall within the previously described OCCR, this proportion was lower for BRCA2 (8/55: 15.4%). BRCA1 variants were not restricted to a particular functional domain, while for BRCA2 20% of PVs were localized within the BRC repeats domain.

Conclusions

In contrast to data from other populations, this study unveils a balanced ratio between BRCA1 and BRCA2 PV in OC pts, probably the result of the BRCA2 Portuguese founder effect. This PV (c.156_157insAlu) is located in exon 3, not previously described as an OCCR. BRCA2 variants were scattered through the gene, while BRCA1 variants were mostly localized in the OCCR. Also, BRC repeats region in BRCA2 appears to be more relevant than the OCCR and CNVs may play a more influential role in BRCA1 than BRCA2 in OC pts, in our cohort.

Legal entity responsible for the study

Instituto Portugues de Oncologia de Lisboa Francisco Gentil.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

Background

The standard third-line treatment of metastatic colorectal cancer (mCRC) is regorafenib, fruquintinib, or TAS-102. However, the efficacy was not satisfied. We conducted a phase Ib /Ⅱa clinical study to evaluate the safety and efficacy of fruquintinib plus cetuximab in mCRC（TPS151, 2021 ASCO GI） This time we reported the phase Ib dose-escalation study results.

Methods

This is a single-center, non-random, prospective, dose-escalation (3 + 3 design), exploratory study. Eligible patients were diagnosed with advanced RAS/BRAF wild-type colorectal cancer and had received at least two prior regimens. The starting dose of fruquintinib was 4 mg once daily (QD) in a 28-day cycle (3 weeks on/1 week off) plus cetuximab. If tolerable, fruquintinib was escalated to 5 mg. If not tolerable, the fruquintinib dose was reduced to 3 mg. The dose of cetuximab is 500mg/m2 every two weeks. 6-9 patients were involved in this study. Adverse events（AEs） were graded according to NCI-CTCAE v4.0. Drug limiting toxicities(DLTs) were evaluated in cycle 1. The response was assessed using RECIST v1.1 q8 wks. The purpose is to confirm the safety and recommended phase II dose (RP2D).

Results

As of Feb 2021, 7 patients were involved. 3 patients received fruquintinib 4 mg and 4 received fruquintinib 5 mg. One DLTs of grade 3 acneiform rash was observed in 1/3 patients at the 4 mg dose. Two DLTs with grade 3 hypertension and two DLTs with grade 3 proteinuria were confirmed at the 5 mg dose level in 3/4 patients. The RP2D is fruquintinib 4 mg QD (3 weeks on/1 week off) plus cetuximab 500mg/m2 every two weeks. The most common treatment-related AEs were hypertension (3/7), proteinuria (3/7), acneiform rash (3/7), creatinine elevation（2/7）, hypoproteinemia (2/7), hemorrhinia (2/7), fatigue (2/7), anemia(2/7), elevated alkaline phosphatase(2/7), elevated aspartic transaminase (1/7) and dry skin (1/7). Evaluation in 7 treated patients showed 4 cases were stable disease (SD) and 3 cases were progressive disease (PD).

Conclusions

Cetuximab combined with fruquintinib showed acceptable anti-tumor activity in CRC with resistance to at least two prior regimens. No unexpected toxicities were observed.

Clinical trial identification

ChiCTR2000038227.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

Background

The carcinoembryonic antigen cell adhesion molecule 1 (CEACAM1) has a number of important roles in the cancer phenotype, including angiogenesis, mediation of neutrophil extracellular trap activity, regulation of NK and CD8+ T-cells, the immune exclusion phenotype of therapy resistance, as well as regulation of TIM3. CM24 is an IgG4 which has been found to block CEACAM1 interactions and has been evaluated in an initial phase I trial (Shapira, R. et al., ASCO 2020) as a single agent at 7 dose levels ranging between 0.01mg/kg and 10mg/kg. No dose limiting toxicities were observed in this study and PK analysis suggested that CM24 doses higher than 10mg/kg should be administered q2w to obtain full receptor occupancy.

Trial design

The phase I/II (Clinical trial: NCT04731467) initiated in February 2021 and encompasses a dose escalation of CM24 from 10 to 20mg/kg administered q2w with nivolumab 480mg q4w for the treatment of refractory cancer patients, with the primary objective to evaluate safety, tolerability, PK and determine the recommended phase II dose (RP2D). During the dose escalation phase, patients are enrolled in dose cohorts in a conventional 3+3 design. This part will be followed by 2 expansion cohorts: the first includes patients with NSCLC refractory to first-line immunotherapy, receiving CM24 RP2D q2w in combination with nivolumab; the second includes patients with metastatic pancreatic adenocarcinoma whose disease progressed after first-line treatment, receiving CM24 RP2D q2w in combination with nab-paclitaxel and nivolumab. The primary objective of the expansion parts is ORR. CEACAM1 measurements in serum, biopsy specimens and TILs as well as tumor and TILs PDL1 levels will be evaluated as potential biomarkers. Blockade of CEACAM1 by CM24 in combination with nivolumab or nivolumab and nab-paclitaxel, may provide patients with refractory malignancies with an important treatment option. Preliminary safety and efficacy data from the study will be presented at the conference.

Clinical trial identification

NCT04731467.

Legal entity responsible for the study

Purple Biotech Ltd. (FameWave Ltd.).

Funding

Purple Biotech Ltd. (FameWave Ltd.).

Disclosure

G. Markel: Financial Interests, Personal, Advisory Board, FameWave Ltd. is a fully owned subsidiary of Purple Biotech Ltd.: Purple Biotech. M. Schickler: Financial Interests, Personal, Full or part-time Employment, FameWave Ltd. is a fully owned subsidiary of Purple Biotech Ltd.: Purple Biotech Ltd. H. Reuveni: Financial Interests, Personal, Full or part-time Employment, FameWave Ltd. is a fully owned subsidiary of Purple Biotech Ltd.: Purple Biotech Ltd. L. Jin: Non-Financial Interests, Sponsor/Funding, BMS is a collaborator in the trial: Purple Biotech Ltd. B. Liang: Financial Interests, Personal, Full or part-time Employment, FameWave Ltd. is a fully owned subsidiary of Purple Biotech Ltd.: Purple Biotech Ltd. All other authors have declared no conflicts of interest.