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Displaying One Session

Channel 2 Proffered Paper session
Date
19.09.2020
Time
14:25 - 16:05
Room
Channel 2
Chairs
  • Samra Turajlic (London, United Kingdom)
  • Núria López-Bigas (Barcelona, Spain)
Proffered Paper - Translational research Proffered Paper session

1928O - Meta-analysis of tumour and T cell intrinsic mechanisms of sensitization to checkpoint inhibition

Presentation Number
1928O
Lecture Time
14:25 - 14:37
Speakers
  • Kevin R. Litchfield (London, United Kingdom)
Room
Channel 2
Date
19.09.2020
Time
14:25 - 16:05

Abstract

Background

A wide number of biomarkers have been associated with immune checkpoint inhibitor (CPI) response to date, however clarity on their reproducibility across larger patient cohorts with defined response criteria is lacking. In addition, systematic pan-tumor analyses may reveal the relative importance of tumour cell intrinsic and microenvironmental features underpinning CPI sensitization.

Methods

Here we collated raw whole exome sequencing and transcriptomic data on >1000 patients treated with checkpoint inhibitor (CPI) treatment across eight tumor types (CPI1000+ cohort), utilizing a uniform bioinformatics pipeline. In addition harmonized RECIST response measures were collected from each study to allow standardized clinical outcome analysis. A systematic literature search was conducted to identify previously published biomarkers, which were then tested across the >1000 patient cohort via meta-analysis. Finally, single cell sequencing of tetramer positive T cells from patient tumour tissue was conducted to further validate results.

Results

Clonal-TMB was the strongest predictor of CPI response, followed by TMB and CXCL9 expression. Subclonal-TMB, somatic copy alteration burden and HLA-evolutionary divergence failed to attain significance. Mutation signature analysis revealed apobec, UV and tobacco associated mutations predictive of CPI response even after correction for TMB. scRNA sequencing of clonal neoantigen-reactive CD8-TILs, combined with bulk RNAseq analysis of CPI responding tumors, identified CCR5 and CXCL13 as T cell-intrinsic mediators of CPI-sensitisation. Finally, combination of biomarkers together into a multi-variate predictive algorithm was shown to attain siginificantly higher AUC scores than TMB alone, in both validation (n=406) and independent test set (n=383).

Conclusions

We find that high clonal mutation burden, apobec/UV/tobacco mutation signatures, together with elevated CXCL9 and CXCL13 expression, as core features marking a tumor as likely to respond to CPI therapy. As biomarker datasets continue to grow in size there is tangible opportunity to build a more complete understanding of CPI response, and identify molecularly defined patient cohorts with high chance of response.

Legal entity responsible for the study

The authors.

Funding

CRUK, MRC.

Disclosure

K.R. Litchfield: Honoraria (self): Roche. S. Quezada: Full/Part-time employment: Achilles Tx. C. Swanton: Advisory/Consultancy: Pfizer; Advisory/Consultancy: Novartis; Advisory/Consultancy: GlaxoSmithKline; Advisory/Consultancy: MSD; Advisory/Consultancy: BMS; Advisory/Consultancy: Celgene; Advisory/Consultancy: AstraZeneca; Advisory/Consultancy: Illumina; Advisory/Consultancy: Genentech; Advisory/Consultancy: Roche-Ventana; Advisory/Consultancy: GRAIL; Advisory/Consultancy: Medicxi; Advisory/Consultancy: Sarah Cannon Research Institute; Shareholder/Stockholder/Stock options: Apogen Biotechnologies; Shareholder/Stockholder/Stock options: Epic Bioscience; Shareholder/Stockholder/Stock options: GRAIL; Leadership role, Shareholder/Stockholder/Stock options: Achilles Therapeutics. All other authors have declared no conflicts of interest.

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Proffered Paper - Translational research Proffered Paper session

1929O - Soluble PD-L1 and circulating CD8+PD1+ and NK cells enclose a highly prognostic and predictive immune effector score in immunotherapy treated NSCLC patients

Presentation Number
1929O
Lecture Time
14:37 - 14:49
Speakers
  • Giulia Mazzaschi (Parma, Italy)
Room
Channel 2
Date
19.09.2020
Time
14:25 - 16:05

Abstract

Background

Upfront criteria to foresee immune checkpoint inhibitors (ICI) efficacy are far from being identified. Thus, we integrated blood descriptors of pro-inflammatory/immunosuppressive or effective anti-tumor response to define predictive immune profiles in ICI-treated advanced NSCLC.

Methods

Peripheral blood (PB) was prospectively collected at baseline from 109 consecutive NSCLC patients undergoing ICI as first or more line treatment. Soluble PD-L1 (sPD-L1) (immunoassay), CD8+PD1+ and NK cells (FACS) were assessed and integrated to generate an Immune effector Score (IeffS). Lung Immune Prognostic Index (LIPI) was also computed by LDH levels and derived Neutrophil-to-Lymphocyte Ratio (dNLR). All these parameters were correlated with survival outcome and response to treatment.

Results

High sPD-L1 and low PB number of CD8+PD1+ and NK cells, individually had a negative impact on both PFS (P<0.001) and OS (P<0.01) as well as on ICI-response (P<0.05). Thus, sPD-L1high, CD8+PD1+low and NKlow were considered as risk factors encompassing IeffS, whose prognostic power outperformed that of single features and slightly exceeded that of LIPI. Accordingly, the absence of these pre-determined risk factors portrayed a favorable IeffS able to identify NSCLC patients with significantly prolonged PFS (median NR vs 2.3 months, P<0.001) and OS (median NR vs 4.1, P<0.001) and greater benefit from ICI (P<0.01). We then combined each individual risk parameter composing IeffS and LIPI (LDHhigh, dNLRhigh), thus defining three distinct prognostic classes: 0-1 vs 2-3 vs ≥ 4 risk factors. A remarkable impact of IeffS-LIPI integration was documented in terms of survival outcome (PFS: HR, 4.61; 95% CI, 2.32-9.18; P<0.001; OS: HR, 4.03; 95% CI, 1.91-8.67; P<0.001) and response to ICI (ROC curve AUC=0.90, 95% CI 0.81-0.97, P<0.001).

Conclusions

Composite risk models based on blood parameters featuring the tumor-host interaction might provide non-invasive prognostic and predictive scores in ICI-treated advanced NSCLC patients.

Legal entity responsible for the study

University Hospital of Parma.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

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Proffered Paper - Translational research Proffered Paper session

Invited Discussant 1928O and 1929O

Lecture Time
14:49 - 14:59
Speakers
  • Daniela S. Thommen (Amsterdam, Netherlands)
Room
Channel 2
Date
19.09.2020
Time
14:25 - 16:05
Proffered Paper - Translational research Proffered Paper session

Q&A and live discussion

Lecture Time
14:59 - 15:09
Speakers
  • Samra Turajlic (London, United Kingdom)
Room
Channel 2
Date
19.09.2020
Time
14:25 - 16:05
Proffered Paper - Translational research Proffered Paper session

1930O - Genomic alterations in solid tumours according to ESMO scale for clinical actionability of molecular targets (ESCAT)

Presentation Number
1930O
Lecture Time
15:09 - 15:21
Speakers
  • Patricia Martin Romano (Villejuif, France)
Room
Channel 2
Date
19.09.2020
Time
14:25 - 16:05

Abstract

Background

Comprehensive genomic profiling (CGP) in advanced solid tumors has led to implement precision medicine in clinical practice. However, genomic alterations (GAs) detected are still not routinely used for therapeutic decision in the majority of the tumor types. The ESMO ESCAT ranks the GAs based on their clinical actionability. Since 2018, our Molecular Tumor Board (MTB) stratified the GAs detected in tissue/liquid biopsy based on ESCAT to guide treatment selection. Based on ESCAT, we aimed to assess clinical actionability of GAs through our MTB.

Methods

Patients (pts) with metastatic solid tumors enrolled in MOSCATO (NCT01566019) and MATCHR (NCT02517892) trials underwent a tumor biopsy at time of relapse. Molecular profiling was performed using next-generation sequencing (NGS), whole-exome sequencing and RNA-sequencing. Clinical actionability of GAs was prospectively assessed at our MTB according to ESCAT tiers. Clinical characteristics and outcome of pts were also collected.

Results

Between Nov 2018 and March 2020, 387 pts underwent a biopsy. Molecular data from 366 pts were interpreted at the MTB. Median age was 61 (range, 24-90); 221 pts (60%) were male. Twenty-seven different tumor types were discussed; the most common were lung (n=117, 32%), gastrointestinal (n=105, 28%) and urological cancer (n=60; 16%). At least one GA was detected in 94% (366/388; 5% failed analysis). Based on ESCAT, GAs were classified according to the tumor type: 20% were tier I [N=72: 25 EGFR mutation (m), 6 ALK rearrangement (r); 6 FGFRr, 4 BRAFV600Em; 9 RETr, 9 RETm; 5 MSI-H; 3 ROS1r; 2 HER2a; 2 BRCAm; 1 METm]; 7% as tier II (n=25: 19 KRASG12Cm; 3 BRAFV600Em [other than lung/melanoma]; 2 METa; 2 HERm); 19% as tier III (n=48) and 16% as tier IV (n=59). Based on ESCAT, CGP reported clinically informative results in 117 pts (32%) and guiding treatment selection in 73 pts (20%). Clinical outcomes (progression free survival; response rate) by ESCAT tier will be presented during the meeting.

Conclusions

ESCAT classification of genomic alterations is attainable in clinical practice through MTB and helps adjusting treatment on both standard of care or investigational settings. Since ESCAT tiers update regularly, a dynamic review of therapeutic choices is advised.

Legal entity responsible for the study

Gustave Roussy.

Funding

Gustave Roussy.

Disclosure

P. Martin Romano: Research grant/Funding (institution): BMS; Research grant/Funding (institution): Astrazeneca. L. Mezquita: Advisory/Consultancy, Speaker Bureau/Expert testimony: Bristol-Myers Squibb. L. Lacroix: Research grant/Funding (institution): AstraZeneca. A. Varga: Research grant/Funding (self), Research grant/Funding (institution): AstraZeneca. C. Baldini: Advisory/Consultancy: Bristol-Myers Squibb. S. Postel-Vinay: Research grant/Funding (self), Research grant/Funding (institution): Boehringer Ingelheim; Travel/Accommodation/Expenses: AstraZeneca. L. Friboulet: Travel/Accommodation/Expenses: AstraZeneca. A. Gazzah: Research grant/Funding (institution), Non-remunerated activity/ies, Principal/sub-Investigator: AstraZeneca. J-C. Soria: Shareholder/Stockholder/Stock options: AstraZeneca. A. Hollebecque: Research grant/Funding (institution), Non-remunerated activity/ies: Bristol-Myers Squibb. B. Besse: Research grant/Funding (institution), Non-remunerated activity/ies: Boehringer Ingelheim. C. Massard: Research grant/Funding (institution), Non-remunerated activity/ies: Principal/sub-Investigator; Research grant/Funding (institution): Research Grants; Non-remunerated activity/ies: Non-financial support (drug supplied). A. Italiano: Advisory/Consultancy, Research grant/Funding (institution): AstraZeneca; Advisory/Consultancy, Research grant/Funding (institution): Bayer; Advisory/Consultancy: Epizyme; Advisory/Consultancy, Research grant/Funding (institution): Roche; Advisory/Consultancy: Philips; Advisory/Consultancy, Research grant/Funding (institution): MSD; Advisory/Consultancy: Springworks; Research grant/Funding (institution): BMS; Research grant/Funding (institution): Merck; Research grant/Funding (institution): PharmaMar. All other authors have declared no conflicts of interest.

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Proffered Paper - Translational research Proffered Paper session

82O - Genomic evolution of metastatic tumours under therapeutic pressure

Presentation Number
82O
Lecture Time
15:21 - 15:33
Speakers
  • Joris Van De Haar (Amsterdam, Netherlands)
Room
Channel 2
Date
19.09.2020
Time
14:25 - 16:05

Abstract

Background

Whole genome sequencing (WGS) is a powerful tool to swiftly and comprehensively identify personalized anticancer treatment options. However, in metastatic cancer, the extent to which somatic genomic profiles are preserved between lesions (heterogeneity in space) and over the course of a patient’s anticancer treatment (heterogeneity in time) remains unclear. Clinicians need guidance on the necessity to repeat genomic characterization in patients with cancer in order to efficiently maximize treatment opportunities.

Methods

WGS data was prospectively collected of 497 longitudinally sampled biopsies from 239 metastatic cancer patients with tumours from 21 different primary sites. Biopsies were taken prior to and after various types of systemic treatments. Available clinical data was used to study associations between the evolution of somatic genomic profiles and clinical characteristics.

Results

During the biopsy interval (median 6.4 months, IQR 3.8-9.6 months), there was a statistically significant but modest (median <10%; mean <20%) increase in the number of mutations, copy number alterations, structural variants and indels. Genomic biomarkers for standard-of-care treatments and clinical trial enrolment could be identified in 22% (n=107) and 51% (n=253) of biopsies, respectively. For 99% (n = 247) of the sequential pairs, the second biopsy did not yield new information regarding standard-of-care genomic treatment indications. Out of 355 biomarkers for clinical trial enrolment identified in the first biopsies, 326 (92%) were also present in the subsequent biopsy. For 224 out of 250 (90%) paired biopsies, the second biopsy did not yield additional biomarkers for clinical trial enrolment. Twenty-eight of the 81 (35%) patients treated with targeted or hormonal therapy between the biopsies gained somatic variants within the gene directly targeted by the drug, revealing known and novel resistance mechanisms.

Conclusions

Our data demonstrates that a one-time WGS analysis during the disease course of a patient with metastatic cancer is (i) sufficient for identifying standard-of-care genomic biomarkers, and (ii) supportive of revealing investigational therapeutic targets that remain present at later stages of the disease.

Legal entity responsible for the study

The authors.

Funding

Josephine Nefkens Stichting, Hartwig Medical Foundation, Oncode Institute, Center for Personalized Cancer Treatment.

Disclosure

All authors have declared no conflicts of interest.

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Proffered Paper - Translational research Proffered Paper session

1189O - Validation of whole genome sequencing in routine clinical practice

Presentation Number
1189O
Lecture Time
15:33 - 15:45
Speakers
  • Kim Monkhorst (Amsterdam, Netherlands)
Room
Channel 2
Date
19.09.2020
Time
14:25 - 16:05

Abstract

Background

Clinical-grade Whole Genome Sequencing (cWGS) is currently being implemented in routine practice. In the WIDE study (WGS Implementation in standard cancer Diagnostics for Every cancer patient), cWGS is performed on a prospective cohort of 1,200 patients (stage IV solid tumors). Here we report the results on feasibility and clinical validity (primary endpoints) of the first 600 patients.

Methods

cWGS was conducted independently of, but in parallel with, validated Standard-of-Care (SOC) diagnostics. For 47% of patients, this included SOC molecular diagnostics (MolDx). cWGS and MolDx results were compared and discussed in a dedicated tumor board. Initial discordances were further evaluated by additional tests.

Results

cWGS was successfully performed in 69% (414/602) of patients with a technical success rate of 96% (414/433). Ineligibility for cWGS was mostly caused by an insufficient number of tumor cells (<20%) in the received biopsy (86%, 145/169). MolDx was performed in 47% (283/602) and was successful in 95% (267/283) of patients. cWGS showed a median turn-around-time (TAT) of 14 days, which decreased incrementally by continuous improvements to the clinical procedure and cWGS pipeline. In total, 480 genomic biomarkers for clinical validation were identified by SOC MolDx. cWGS showed an error rate of 4.2% (20/480) compared to a SOC MolDx error rate of 1% (5/480). Most of the biomarkers that were not reported by cWGS (19 of 20) were present in the raw data but not reliably identified due to very low variant allele frequencies. Improvements to further increase the sensitivity are currently being implemented with an anticipated reduction of the cWGS error rate to 2%. Overall, cWGS identified a clinically actionable (routine practice and experimental) biomarker in 74% of all patients tested. Compared to SOC MolDx, cWGS identified one or more additional treatment options in 69% (197/287) of patients. Interestingly, in patients that were not tested by SOC MolDx, actionable variants were identified in 60% (76/126).

Conclusions

Based on the first 600 patients of the WIDE study, cWGS was found to be clinically feasible in routine molecular diagnostics in a comprehensive cancer center setting and has added value by providing additional treatment options for the majority of patients.

Legal entity responsible for the study

Gerrit Meijer, Emile Voest and Kim Monkhorst.

Funding

The Netherlands Organisation for Health Research and Care innovation (ZonMW) and Hartwig Medical Foundation.

Disclosure

K. Monkhorst: Honoraria (self), Advisory/Consultancy, Research grant/Funding (self), Travel/Accommodation/Expenses: F. Hoffmann-La Roche; Honoraria (self), Advisory/Consultancy, Research grant/Funding (self): AstraZeneca; Research grant/Funding (self): PDGx; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: MSD; Advisory/Consultancy: Pfizer; Advisory/Consultancy: BMS; Advisory/Consultancy: Abbvie; Advisory/Consultancy: Diaceutics; Travel/Accommodation/Expenses: Takeda. All other authors have declared no conflicts of interest.

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Proffered Paper - Translational research Proffered Paper session

Invited Discussant 1930O, 82O, and 1189O

Lecture Time
15:45 - 15:55
Speakers
  • Núria López-Bigas (Barcelona, Spain)
Room
Channel 2
Date
19.09.2020
Time
14:25 - 16:05
Proffered Paper - Translational research Proffered Paper session

Q&A and live discussion

Lecture Time
15:55 - 16:05
Speakers
  • Samra Turajlic (London, United Kingdom)
Room
Channel 2
Date
19.09.2020
Time
14:25 - 16:05