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1123O - Evaluation of cell-free DNA approaches for multi-cancer early detection
- Minetta C. Liu (Rochester, MN, United States of America)
Abstract
Background
In the first substudy of the Circulating Cell-free Genome Atlas (CCGA) study (NCT02889978; Sep 2016), cfDNA multi-omics were evaluated in prototype cfDNA-based MCED tests.
Methods
Plasma and matched white blood cells (WBCs) were collected and sequenced from CCGA participants. Where available, tumor biopsies were also sequenced. Six cfDNA-omics were used: whole-genome (WG) methylation data from WG bisulfite sequencing (30×); small somatic variant data from error-corrected targeted sequencing (TS; 60,000×); and somatic copy-number aberration (SCNA), fragment length, fragment endpoint, and allelic imbalance data from WG sequencing (WGS; 30×). Samples were split into independent training (T) and validation (V) sets and 10 classifiers were trained to detect solid cancer (carcinomas, sarcomas, lymphomas): 1 per -omic, 2 corrected for clonal hematopoiesis (CH) using germline DNA from paired WBC sequencing, 1 pan-omics, 1 clinical data only. These were assessed for cancer detection and clinical limit of detection (cLOD), which was estimated as the probability of detecting cancer as a function of circulating tumor fraction (cTF) using matched tumor biopsies. Three additional classifiers (each using WG methylation, TS, or SCNA) were trained to predict cancer signal origin (CSO) and were assessed for accuracy.
Results
Of 2,800 participants, 2,261 (1,414 T; 847 V) had analyzable results. T and V results were similar; all results here are for V. cTF accounted for >72% of the variance in cancer detection scores. The cLOD was >1.5-fold lower for WG methylation than any WGS or TS classifier (even with WBC CH correction for WGS/TS). CSO prediction was >1.8-fold more accurate using WG methylation than TS or SCNA.
Conclusions
The strong correlation between cTF and cancer detection performance suggests that cLOD may be an attractive metric for comparing MCED test performance at equal specificity. Here, a WG methylation assay outperformed WGS or TS without needing additional WBC sequencing for CH. These data informed the design of a significantly improved targeted methylation MCED test for further CCGA substudies to support clinical use.
Clinical trial identification
NCT02889978.
Editorial acknowledgement
Medical writing assistance was provided by Alexis Fedorchak (GRAIL, Inc.).
Legal entity responsible for the study
GRAIL, Inc.
Funding
GRAIL, Inc.
Disclosure
M.C. Liu: Financial Interests, Institutional, Advisory Board, The Mayo Clinic was compensated for MCL’s and DDT’s, advisory board activities for GRAIL, Inc. A. Jamshidi: Financial Interests, Personal, Full or part-time Employment: GRAIL, Inc.; Financial Interests, Personal, Stocks/Shares: GRAIL, Inc.; Financial Interests, Personal, Stocks/Shares: Illumina, Inc. E.A. Klein: Financial Interests, Personal, Advisory Role: GRAIL, Inc.; Financial Interests, Personal, Advisory Role: Genomic Health; Financial Interests, Personal, Advisory Role: Genome Dx. O. Venn, E. Hubbell, J.F. Beausang, N. Zhang: Financial Interests, Personal, Full or part-time Employment: GRAIL, Inc.; Financial Interests, Personal, Stocks/Shares: GRAIL, Inc. K.N. Kurtzman, C. Hou: Financial Interests, Personal, Full or part-time Employment: GRAIL, Inc.; Financial Interests, Personal, Stocks/Shares: GRAIL, Inc.; Financial Interests, Personal, Stocks/Shares: Illumina, Inc. D.D. Thiel: Financial Interests, Institutional, Advisory Board, The Mayo Clinic was compensated for MCL’s and DDT’s, advisory board activities for GRAIL, Inc. A.H. Bryce: Financial Interests, Personal, Advisory Role: Pfizer; Financial Interests, Personal, Advisory Role: Merck; Financial Interests, Personal, Advisory Role: Bayer; Financial Interests, Personal, Advisory Role: Astellas Pharmaceuticals. M.V. Seiden: Financial Interests, Personal, Full or part-time Employment: McKesson Corporation; Financial Interests, Personal, Stocks/Shares: McKesson Corporation; Financial Interests, Personal, Advisory Role: GRAIL, Inc. C. Swanton: Financial Interests, Personal, Stocks/Shares: GRAIL, Inc; Financial Interests, Personal, Stocks/Shares: Epic Biociences; Financial Interests, Personal, Stocks/Shares: Apogen Biotech; Financial Interests, Personal and Institutional, Research Grant: Pfizer; Financial Interests, Personal and Institutional, Research Grant: AstraZeneca; Financial Interests, Personal, Advisory Role: Roche Ventana; Financial Interests, Personal, Advisory Role: Celgene; Financial Interests, Personal, Advisory Role: Pfizer; Financial Interests, Personal, Advisory Role: Novartis; Financial Interests, Personal, Advisory Role: Genentech; Financial Interests, Personal, Advisory Role: BMS; Financial Interests, Personal and Institutional, Member of the Board of Directors: Achilles Therapeutics. All other authors have declared no conflicts of interest.
1757O - Early reduction in ctDNA, regardless of best RECIST response, is associated with overall survival (OS) on tebentafusp in previously treated metastatic uveal melanoma (mUM) patients
- Alexander N. Shoushtari (New York, United States of America)
Abstract
Background
Tebentafusp (tebe), an investigational TCR–anti-CD3 bispecific fusion protein that targets gp100 and activates T cells, has shown OS benefit in 1st line mUM. OS was improved in patients (pts) regardless of RECISTv1.1 best response, suggesting better surrogate efficacy endpoints are needed.
Methods
2L+ HLA-A*02:01+ mUM pts were treated weekly with 68mcg tebe after intra-patient dose escalation (NCT02570308). RECISTv1.1 was assessed by an independent radiographic committee. Serum samples (N=118) collected at baseline (BL) and at weeks (wks) 5, 9 on tebe were analyzed for ctDNA using a targeted mPCR-NGS assay for mutations in 15 genes including mUM oncogenes GNAQ, GNA11, SF3B1, CYSLTR2, PLCB4 and EIF1AX. 0.1-3 log reductions in mean tumour molecules (MTM) per ml of serum observed on treatment were tested for association with OS.
Results
109/118 (92%) of pts had detectable ctDNA. MTM at BL was correlated with tumor burden as assessed by sum of longest diameters (Spearman’s r=0.61, P=10-10). By wk 9, in 99 pts with BL and on-treatment MTM measurements, any (>0) ctDNA reduction was observed in 69 (70%). In 97 pts that were evaluable by RECISTv1.1, any ctDNA reduction was observed in 31/48 with progressive disease (PD), 34/45 with stable disease (SD) and 2/4 with partial response (PR). Magnitude of ctDNA reduction by wk 9 was strongly associated with improvement in OS (R2=0.87, P<0.0001): 0.1 log reduction hazard ratio HR 0.8; 0.5 log reduction HR 0.5; 1 log reduction HR 0.4; 2 log reduction HR 0.3, 3 log reduction HR 0.2 and undetectable ctDNA (clearance) HR 0.1. 1 yr OS was 100% in pts with ctDNA clearance (N=14) vs 57% in those with increased ctDNA (N=30). Best overall response among those with ctDNA clearance was PD in 4 (29%), SD in 8 (57%) and PR in 1 (7%).
Conclusions
ctDNA was detected in most mUM pts, associated with tumor burden at BL and reduced in 70% of pts on tebe, despite a RECIST response rate of <10%. ctDNA reduction as early as 9 wks on tebe was strongly associated with improved OS, even in pts with RECIST PD or SD. Early ctDNA reduction may be a better surrogate of tebe efficacy than RECIST objective response in mUM.
Clinical trial identification
NCT02570308.
Legal entity responsible for the study
Immunocore Ltd.
Funding
Immunocore Ltd.
Disclosure
A.N. Shoushtari: Financial Interests, Institutional, Research Grant: Immunocore Ltd.; Financial Interests, Institutional, Research Grant: BMS; Non-Financial Interests, Personal, Other: Castle Biosciences; Financial Interests, Institutional, Research Grant: Xcovery; Financial Interests, Institutional, Research Grant: GSK; Financial Interests, Institutional, Research Grant: Novartis; Financial Interests, Institutional, Research Grant: Pfizer. L. Collins: Financial Interests, Institutional, Full or part-time Employment: Immunocore Ltd. E. Espinosa: Non-Financial Interests, Personal, Advisory Role: BMS; Non-Financial Interests, Personal, Advisory Role: MSD; Non-Financial Interests, Personal, Advisory Role: Novartis; Non-Financial Interests, Personal, Advisory Role: Pierre Fabre; Financial Interests, Personal, Research Grant: Roche; Non-Financial Interests, Institutional, Principal Investigator: Immunocore. H. Sethi: Financial Interests, Institutional, Full or part-time Employment: Natera Inc.; Financial Interests, Institutional, Stocks/Shares: Natera Inc.. S. Stanhope: Financial Interests, Institutional, Full or part-time Employment: Immunocore Ltd. S. Abdullah: Financial Interests, Institutional, Full or part-time Employment: Immunocore Ltd. A. Ikeguchi: Non-Financial Interests, Institutional, Principal Investigator: Immunocore. K. Ranade: Financial Interests, Institutional, Full or part-time Employment: Immunocore Ltd. O. Hamid: Non-Financial Interests, Personal, Advisory Board: Aduro; Non-Financial Interests, Personal, Advisory Board: Akeso; Non-Financial Interests, Personal, Advisory Board: Amgen; Non-Financial Interests, Personal, Advisory Board: BeiGene; Non-Financial Interests, Personal, Advisory Board: Bioatla; Non-Financial Interests, Personal, Invited Speaker: BMS; Non-Financial Interests, Personal, Advisory Board: BMS; Non-Financial Interests, Personal, Advisory Board: GSK; Non-Financial Interests, Personal, Advisory Board: Idera; Non-Financial Interests, Personal, Advisory Board: Immunocore; Non-Financial Interests, Personal, Advisory Board: Incyte; Non-Financial Interests, Personal, Advisory Board: Janssen; Non-Financial Interests, Personal, Advisory Board: Merck; Non-Financial Interests, Personal, Advisory Board: Nextcure; Non-Financial Interests, Personal, Invited Speaker: Novartis; Non-Financial Interests, Personal, Advisory Board: Novartis; Non-Financial Interests, Personal, Invited Speaker: Pfizer; Non-Financial Interests, Personal, Advisory Board: Pfizer; Non-Financial Interests, Personal, Advisory Board: Roche Genentech; Non-Financial Interests, Personal, Advisory Board: Sanofi / Regeneron; Non-Financial Interests, Personal, Invited Speaker: Sanofi / Regeneron; Non-Financial Interests, Personal, Advisory Board: Seagen; Non-Financial Interests, Personal, Advisory Board: Tempus; Non-Financial Interests, Personal, Advisory Board: Zelluna; Non-Financial Interests, Institutional, Principal Investigator: Aduro; Non-Financial Interests, Institutional, Principal Investigator: Akeso; Non-Financial Interests, Institutional, Principal Investigator: Amgen; Non-Financial Interests, Institutional, Principal Investigator: Arcus; Non-Financial Interests, Institutional, Principal Investigator: Bioatla; Non-Financial Interests, Institutional, Principal Investigator: BMS; Non-Financial Interests, Institutional, Principal Investigator: CytomX; Non-Financial Interests, Institutional, Principal Investigator: Exelixis; Non-Financial Interests, Institutional, Principal Investigator: GSK; Non-Financial Interests, Institutional, Principal Investigator: Idera; Non-Financial Interests, Institutional, Principal Investigator: Immunocore; Non-Financial Interests, Institutional, Principal Investigator: Incyte; Non-Financial Interests, Institutional, Principal Investigator: Iovance; Non-Financial Interests, Institutional, Principal Investigator: Merck; Non-Financial Interests, Institutional, Principal Investigator: Merck Serono; Non-Financial Interests, Institutional, Principal Investigator: Moderna; Non-Financial Interests, Institutional, Principal Investigator: Nextcure; Non-Financial Interests, Institutional, Principal Investigator: Novartis; Non-Financial Interests, Institutional, Principal Investigator: Pfizer; Non-Financial Interests, Institutional, Principal Investigator: Roche Genentech; Non-Financial Interests, Institutional, Principal Investigator: Sanofi / Regeneron; Non-Financial Interests, Institutional, Principal Investigator: Seagen; Non-Financial Interests, Institutional, Principal Investigator: Torque; Non-Financial Interests, Institutional, Principal Investigator: Zelluna.
Invited Discussant 1123O and 1757O
- Christian D. Rolfo (Baltimore, United States of America)
Q&A and live discussion
- Christian D. Rolfo (Baltimore, United States of America)
1758O - Neoadjuvant pembrolizumab in localized/locally advanced solid tumors with mismatch repair deficiency
- Kaysia Ludford (Houston, United States of America)
Abstract
Background
Pembrolizumab (pembro) significantly improves clinical outcomes in advanced/metastatic microsatellite instability high (MSI-H)/deficient mismatch repair (dMMR) solid tumors. This study evaluates pembro in the neoadjuvant space with the potential for an organ-sparing approach.
Methods
This is a phase 2 open-label, single center trial of MSI-H/dMMR non-metastatic solid tumors with localized unresectable or high risk resectable (defined as ≥ 20% recurrence) with measurable disease. Treatment is Pembro 200mg every 3 wks for 8 cycles followed by surgical resection with option to continue therapy for 18 cycles followed by observation. First restaging is at 6 wks and includes baseline and 3-week 70-gene ctDNA assessment. To continue on study, patients are required to have PR/CR, SD with tumor shrinkage or SD with decline in ctDNA. The co-primary endpoints are safety and pathological complete response (pCR). Key secondary endpoints are response rate and organ-sparing at one year for patients who declined surgery.
Results
Between 10/2019 and 3/2021, 35 pts were enrolled and study has completed enrollment. Tumor types included 27 CRC and 8 non-CRC: endometrial, gastric, meningioma, 2 duodenal, ampullary and 2 pancreatic. Median follow-up was 9 months (range 0.1 - 17). Among 32 evaluable pts, best ORR was 75% (CR 25% , PR 50%), SD 22% and PD 3%. Luminal endoscopic response was seen in 17/19 (89%) pts. Among 8 (23%) pts who underwent surgery, pCR was seen in 4. At present non-operative approach was chosen by 8 (23%) pts with 1-year organ-sparing seen in 2/2 evaluable pts. Treatment-related grade 3/4 immune adverse events were seen in 3 (9%) pts (transaminitis, diarrhea and type 1 diabetes). Baseline ctDNA mutations were present in 20 (57%) pts and at 3 weeks declined in 15 (75%), unchanged in 1, no paired 3 week sample in 1, and increased in 3. Tumor microenvironment immune analysis is ongoing and will be presented.
Conclusions
Neoadjuvant pembrolizumab in dMMR/MSI-H cancers is safe and resulted in high rates of radiographic and endoscopic response which has implications for organ-sparing strategies. Non-operative management of dMMR/MSI-H localized solid tumors should be further investigated.
Clinical trial identification
NCT04082572.
Legal entity responsible for the study
The authors.
Funding
Merck.
Disclosure
All authors have declared no conflicts of interest.
1124O - Prediction of distant relapse in patients with invasive breast cancer from deep learning models applied to digital pathology slides
- Ingrid J. Garberis (Villejuif, France)
Abstract
Background
Breast cancer (BC) has a favorable long-term prognosis, with an estimated average 5-year survival rate of 87%. Nevertheless, 10% of patients relapse after initial treatment each year. To better identify these patients, Owkin and Gustave Roussy conceived a diagnostic tool that applies deep learning (DL) to whole slide images (WSI) and clinical data, that could work as an aid in therapeutic decision.
Methods
1437 patients diagnosed with ER+HER2- BC between 2005 and 2013 were included. All patients underwent surgical resection, with full follow-up and an available hematoxylin-eosin stained glass slide, which was digitized, preprocessed and cut into small patches called
Results
The prediction of 5-year survival based solely on BV yielded an AUC of 0.77. DL algorithm based solely on WSI yields an AUC of 0.77. A model based on EV yielded an AUC of 0.80. Combining BV with our DL algorithm resulted in an improved AUC of 0.81. This model also predicted relapse in ER+HER2-N0 (AUC=0.77) and ER+HER2-N+ (AUC=0.80) subgroups. Validation will be carried out on large independent cohorts from external health care centers.
Conclusions
DL applied to WSI could predict the risk of relapse in early ER+HER2- BC patients. Coupled to BV, our model could be a promising tool for treatment decision-making at low cost. Our next steps are to unravel the most predictive tiles to discover new biomarkers, and to develop novel models for prediction of relapse, as an alternative to onerous techniques such as immunohistochemistry or molecular tests.
Legal entity responsible for the study
Gustave Roussy.
Funding
Owkin.
Disclosure
C. Saillard, B. Schmauch, V. Aubert, A. Jaeger, A. de Lavergne, A. Kamoun, P. Courtiol: Financial Interests, Institutional, Full or part-time Employment: Owkin. F. André: Financial Interests, Institutional, Other, speaker/advisor: Roche; Financial Interests, Institutional, Other, speaker/advisor: AstraZeneca; Financial Interests, Institutional, Other, speaker/advisor: Daiichi Sankyo; Financial Interests, Institutional, Other, speaker/advisor: Pfizer; Financial Interests, Institutional, Other, speaker/advisor: Novartis; Financial Interests, Institutional, Other, speaker/advisor: Lilly. All other authors have declared no conflicts of interest.
Invited Discussant 1758O and 1124O
- Sherene Loi (Melbourne, VIC, Australia)
Q&A and live discussion
- Sherene Loi (Melbourne, VIC, Australia)