ESMO Supporter 2018

Displaying One Session

ICM - Room 14b Poster Discussion session
Date
21.10.2018
Time
09:15 - 10:30
Location
ICM - Room 14b
Chairs
  • Joaquin Mateo (Barcelona, ES)
  • Joe O'Sullivan (Belfast, GB)
  • Aristotelis Bamias (Athens, GR)
Poster Discussion session - Genitourinary tumours, prostate Poster Discussion session

Session DOI

Lecture Time
09:15 - 09:15
Location
ICM - Room 14b, ICM München, Munich, Germany
Date
21.10.2018
Time
09:15 - 10:30
Poster Discussion session - Genitourinary tumours, prostate Poster Discussion session

793PD - Preliminary results from TRITON2: a phase 2 study of rucaparib in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) associated with homologous recombination repair (HRR) gene alterations

Presentation Number
793PD
Lecture Time
09:15 - 09:15
Speakers
  • Wassim Abida (New York, US)
Location
ICM - Room 14b, ICM München, Munich, Germany
Date
21.10.2018
Time
09:15 - 10:30

Abstract

Background

Treatment options for mCRPC following androgen deprivation and taxane therapy are limited. Preclinical and limited clinical data suggest efficacy of PARP inhibition in HRR-deficient PCa.

Methods

TRITON2 (NCT02952534; target enrolment, 157 pts) is evaluating rucaparib 600 mg BID in pts with a deleterious germline or somatic alteration in BRCA1, BRCA2 or 1 of 13 other prespecified HRR genes. Pts who progressed on 1–2 lines of androgen receptor–directed therapy and 1 prior line of taxane-based chemotherapy for mCRPC are eligible. The primary endpoint is centrally assessed confirmed objective response rate per modified RECIST v1.1/PCWG3 for pts with measurable disease and confirmed prostate-specific antigen (PSA) response (≥50% decrease) in pts without measurable disease. PSA response in all pts is a secondary endpoint.

Results

At the 6 Mar 2018 data cutoff date, 52 pts were treated with rucaparib. Median duration of follow-up was 3.7 mo (range, 1.0–12.6). Twenty-six pts (50%) had a BRCA1/2 alteration (BRCA pts), 12 had a CDK12 alteration, 10 had an ATM alteration and 4 had an alteration in another HRR gene. Prior therapies included docetaxel (88.5%), enzalutamide (82.7%), abiraterone (71.2%) and cabazitaxel (11.5%). Forty-four pts (84.6%) had bone metastases; 33 (63.5%) and 17 pts (32.7%) had nodal and visceral metastases, respectively. Among BRCA pts, 21 (80.8%) remain on study (median treatment duration, 16.1 wk; range, 4.1–36.9). Eleven of 23 evaluable BRCA pts had a confirmed PSA response (47.8%; 95% CI, 26.8–69.4). Five of 11 evaluable BRCA pts had a confirmed investigator-assessed RECIST/PCWG3 response (45.5%; 95% CI, 16.7–76.6). Overall, the most common treatment-emergent adverse events (TEAEs) included nausea (48.1%; grade ≥3, 3.8%) and asthenia/fatigue (44.2%; grade ≥3, 1.9%). One (1.9%) pt discontinued due to a TEAE; no deaths were reported.

Conclusions

Rucaparib has encouraging antitumour activity in mCRPC pts with a deleterious alteration in BRCA1 or BRCA2. Updated data from current and newly enrolled pts will be presented, including from pts with other gene alterations.

Clinical trial identification

NCT02952534.

Legal entity responsible for the study

Clovis Oncology, Inc.

Funding

Clovis Oncology, Inc.

Editorial Acknowledgement

Writing and editorial support, funded by Clovis Oncology, Inc. (Boulder, CO, USA) was provided by Nathan Yardley, PhD, and Shannon Davis of Ashfield Healthcare Communications (Middletown, CT, USA).

Disclosure

W. Abida: Consulting, Advisory role: Clovis Oncology; Honoraria: Caret Healthcare; Research funding: AstraZeneca, Zenith Epigenetics. N.J. Vogelzang: Consulting, Advisory role: Caris, Sanofi Aventis, Bayer, Pfizer, Janssen, AstraZeneca, Astellas; Stock options owner: Caris; Editor: Up-To-Date. R.J. Amato: Consulting, Advisory role, Speaker bureaus: Jansen, Astellas/Pfizer (Medivation), Novartis. A. Hussain: Consulting, Advisory role: Bayer, Bristol-Myers Squibb, AstraZeneca. A. Patnaik: Consulting, Advisory role: Janssen; Research funding: Bristol-Myers Squibb, GlaxoSmithKline. D. Petrylak: Consulting, Advisory role: Bayer, Bellicum Pharmaceuticals, Dendreon, Johnson & Johnson, Exelixis, Ferring, Millenium, Medivation, Pfizer, Roche, Sanofi and Tyme Pharmaceuticals; Expert testimony: Celgene, Sanofi; Research funding: Oncogenex, Progenics, Johnson & Johnson, Dendreon, Sanofi, Endocyte, Genentech, Merck, Astellas Medivation, Novartis, Agensys, AstraZeneca, Bayer, Lilly, Innocrin Pharma, MedImmune, Millineum, Pfizer, Roche, Sotio; Stock owner, Other ownership interests: Bellicum Pharmaceuticals and Tyme, Inc. C.J. Ryan: Consulting, Advisory role: Bayer, Millennium; Honoraria: Janssen Oncology, Astellas Pharma; Research funding: BIND Biosciences, Karyopharm Therapeutics, Novartis. J. Zhang: Consulting, Advisory role, Speaker’s bureaus: AstraZeneca, Sanofi; Research funding: AstraZeneca, Astellas Pharma, Bayer. A.D. Simmons, D. Despain, M. Collins, T. Golsorskhi: Employee, Stock owner, Stock option owner: Clovis Oncology. H.I. Scher: Consulting, Advisory role: AstraZeneca, Astellas Pharma, Bristol-Myers Squibb, Celgene, Endocyte, Exelixis, Endo Pharmaceuticals, Ferring, Foundation Medicine, Genentech, Janssen, OncologySTAT, Palmetto GBA, Pfizer, Sanofi, Takeda, Ventana Medical Systems, BIRB-Copernicus Group, Medivation; Speaker’s bureau: WebMD; Travel, accommodation: Exelixis, Janssen, Sanofi, Endocyte, AstraZeneca, Genentech, Bristol-Myers Squibb, Celgene, Pfizer, Takeda, Ferring, WIRB-Copernicus Group, and Astellas Pharma; Honoraria: Chugai Pharma; Research funding: BIND Biosciences, Exelixis, Janssen, Medivation, Janssen Diagnostics. S. Chowdhury: Consulting, Advisory role, Speaker’s bureaus: Clovis Oncology, Sanofi, Pfizer, Astellas Pharma, Janssen; Honoraria: GlaxoSmithKline, Novartis; Research funding: Sanofi, Johnson & Johnson. All other authors have declared no conflicts of interest.

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Poster Discussion session - Genitourinary tumours, prostate Poster Discussion session

794PD - Prospective comprehensive genomic profiling (CGP) of 3,343 primary and metastatic site prostate tumors

Presentation Number
794PD
Lecture Time
09:15 - 09:15
Speakers
  • Siraj M. Ali (Cambridge, US)
Location
ICM - Room 14b, ICM München, Munich, Germany
Date
21.10.2018
Time
09:15 - 10:30

Abstract

Background

Sequencing of prostate cancer has identified genomic alterations (GAs) with therapeutic implications (PMID: 29694820). To more fully inform targeted treatment strategies, we performed prospective CGP on 3,343 prostate tumors to better define the spectrum of GAs and assess signatures of genomic instability in primary and metastatic site tumors.

Methods

Prostate cancer samples (1,525 primary site, 1,818 metastatic site) were assessed by hybrid capture-based CGP for all exons of 395 genes and select introns for 31 genes. Results were analyzed for base substitutions, short insertions/deletions (indels), rearrangements, and copy number alterations, as well as genomic signatures including genome-wide loss of heterozygosity (LOH), microsatellite instability (MSI) status and tumor mutational burden (TMB).

Results

There was an average of 4.6 GAs per tumor. Frequently altered genes were TP53 (45%), PTEN (33%), TMPRSS2-ERG (31%) and AR (23%). Targetable BRAF/RAF1 fusions were mutually exclusive with ETS fusions. The PI3K (41%), G1/S cell cycle (24%) and WNT (16%) pathways were frequently altered. DNA repair GAs were frequent and included homologous recombination repair (HRR) (22%), Fanconi Anemia (4%), and mismatch repair (MMR) (4%) pathway GAs; 39% of DNA repair mutations were predicted to be germline. BRCA1/2, ATR and FANCA GAs were associated with high genome-wide LOH. Overall median TMB was low (2.6 mutations/Mb), although a subset (3%) were TMB-High; 71% of TMB-High cases were MSI-High. Metastatic tumors were enriched in AR, LYN, 11q13 amplicon (CCND1/FGF19/FGF4/FGF3), MYC, NCOR1, CDKN2A, RB1, and CTNNB1 GAs. AR GAs associated with anti-androgen resistance were frequent in metastatic site samples including amplification (28%), mutations (12%), and rearrangements (2%).

Conclusions

Routine CGP frequently identified GAs that may inform targeted therapy or trial selection for metastatic prostate cancer: PI3K pathway GAs, HRR pathway GAs, and MSI-High/TMB-High genomic signatures may inform PI3K/AKT inhibitor targeted therapy, PARP inhibitors, and immunotherapy, respectively. DNA repair mutations were frequently germline, and patients with such mutations may require further testing and genetic counselling.

Legal entity responsible for the study

Foundation Medicine.

Funding

Has not received any funding.

Disclosure

S.M. Ali, J. Chung, N. Dewal, L.M. Gay, Y. He, E.S. Sokol, S.Z. Millis, J.K. Killian, A.B. Schrock, V.A. Miller, J.S. Ross: Employee: Foundation Medicine. All other authors have declared no conflicts of interest.

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Poster Discussion session - Genitourinary tumours, prostate Poster Discussion session

795PD - Genomic profiling of circulating tumour DNA (ctDNA) and tumour tissue for the evaluation of rucaparib in metastatic castration-resistant prostate cancer (mCRPC)

Presentation Number
795PD
Lecture Time
09:15 - 09:15
Speakers
  • Simon Chowdhury (London, GB)
Location
ICM - Room 14b, ICM München, Munich, Germany
Date
21.10.2018
Time
09:15 - 10:30

Abstract

Background

The phase 2 TRITON2 (NCT02952534) and phase 3 TRITON3 (NCT02975934) studies are evaluating the poly (ADP-ribose) polymerase inhibitor rucaparib in patients (pts) with mCRPC who have a deleterious germline or somatic mutation in BRCA1, BRCA2, ATM, or other homologous recombination repair (HRR) gene. Here we present initial results from central genomic screening of plasma ctDNA and tissue samples in TRITON2 and TRITON3.

Methods

Plasma samples were profiled for genomic alterations (GAs) in 64 genes using a Foundation Medicine, Inc. (FMI), next-generation sequencing (NGS) assay. FFPE tumour tissue samples were profiled for GA in 395 genes, genome-wide loss of heterozygosity (LOH), and tumour mutational burden (TMB) using an FMI NGS assay.

Results

As of 28 Feb 2018, ctDNA samples from 300 pts with mCRPC and disease progression were sequenced. Cell free DNA burden was significantly higher (P<0.0001) in pts who had progressed on prior androgen receptor (AR)-directed therapy and taxane-based chemotherapy (TRITON2) vs on AR-directed therapy alone (TRITON3). Prevalence of TP53 GAs in ctDNA was similar in TRITON2 (45.5%) and TRITON3 (46.0%). A deleterious GA was detected in BRCA1 (2.0%), BRCA2 (10.7%), or ATM (8.8%). We also sequenced 500 pts’ tissue samples (Gleason score ≥8, 78%) from primary prostate cancer tumours (74%) or metastases (19%). A deleterious GA in BRCA1 (1.6%), BRCA2 (8.2%), or ATM (5.8%) was observed in 15.6% of samples; of these GAs, 56% were biallelic. A deleterious GA in CDK12 or 1 of 11 other HRR genes was detected in 5.6% and 6.4% of pts. Genome-wide LOH was determined for 339 BRCAwt tissue samples and was significantly higher (P<0.0001) in metastatic (median, 9.1%) compared to primary (median, 7.0%) samples, suggesting a higher degree of DNA damage in more advanced disease. Median TMB observed in 443 tumour samples was 3.5 mutations per megabase, with 81% having low, 18% intermediate, and 1% high TMB.

Conclusions

Genomic profiling of both ctDNA and FFPE tumour tissue samples using NGS successfully identified pts with a GA in an HRR gene for the evaluation of rucaparib in mCRPC. Additional and updated genomic analyses will be presented.

Clinical trial identification

NCT02952534.

Legal entity responsible for the study

Clovis Oncology, Inc.

Funding

Clovis Oncology, Inc.

Editorial Acknowledgement

Writing and editorial support, funded by Clovis Oncology, Inc. (Boulder, CO, USA) was provided by Nathan Yardley, PhD, and Shannon Davis of Ashfield Healthcare Communications (Middletown, CT, USA).

Disclosure

S. Chowdhury: Consulting, Advisory role, Speakers bureaus: Clovis Oncology, Sanofi, Pfizer, Astellas Pharma, Janssen; Honoraria: GlaxoSmithKline, Novartis; Research funding: Sanofi, Johnson & Johnson. J.M. Piulats: Consulting, Advisory role: Clovis Oncology, Astellas, Janssen, Bayer, Bristol-Myers Squibb, Merck Sharp & Dohme, Merck Serono, Pfizer, Roche, Novartis; Research funding: Merck Serono, Bristol-Myers Squibb, Pfizer, Janssen, Astellas. D. Morris: Consulting, Advisory role, Speakers bureaus: Janssen, Dendreon, GenomeDx, Myriad, Pacific Edge Diagnostics, Astellas; Support for scientific study or clinical trial: Janssen, Dendreon, Bayer, Myriad, Clovis Oncology, and Astellas. A. Hussain: Consulting, Advisory role: Bayer, Bristol-Myers Squibb, AstraZeneca. E. Pintus: Consulting or advisory role: Clovis Oncology; Honoraria: Astellas, travel, grant support: Clovis, Janssen, Astellas. A. Benjelloun: Consulting, Advisory role: Janssen, Astellas, Bristol-Myers Squibb. M.E. Gross: Research support: Clovis Oncology, Myriad, Janssen. A. Loehr, A.D. Simmons, S.P. Watkins: Employee, Stock owner, Stock option Owner: Clovis Oncology. W. Abida: Consulting, Advisory role: Clovis Oncology; Honoraria: Caret Healthcare; Research funding: AstraZeneca, Zenith Epigenetics. All other authors have declared no conflicts of interest.

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Poster Discussion session - Genitourinary tumours, prostate Poster Discussion session

Invited Discussant 793PD, 794PD and 795PD

Lecture Time
09:15 - 09:30
Speakers
  • Joaquin Mateo (Barcelona, ES)
Location
ICM - Room 14b, ICM München, Munich, Germany
Date
21.10.2018
Time
09:15 - 10:30
Poster Discussion session - Genitourinary tumours, prostate Poster Discussion session

Q&A led by Discussant

Lecture Time
09:30 - 09:40
Location
ICM - Room 14b, ICM München, Munich, Germany
Date
21.10.2018
Time
09:15 - 10:30
Poster Discussion session - Genitourinary tumours, prostate Poster Discussion session

796PD - Detection of circulating tumor DNA in de novo metastatic castrate sensitive prostate cancer

Presentation Number
796PD
Lecture Time
09:40 - 09:40
Speakers
  • Werner J. Struss (Vancouver, CA)
Location
ICM - Room 14b, ICM München, Munich, Germany
Date
21.10.2018
Time
09:15 - 10:30

Abstract

Background

De novo metastatic castrate sensitive prostate cancer (mPC) represents approximately 10% of prostate cancer diagnoses but almost 50% of mPC related deaths. Biomarkers are required to guide therapy intensification at time of diagnosis, but scant tumor material is available since most patients do not undergo prostatectomy. Plasma circulating tumor DNA (ctDNA) is a promising minimally-invasive biomarker in castration-resistant disease but remains untested in castrate-sensitive disease.

Methods

We collected plasma cell-free DNA (cfDNA) at or near time of diagnosis from 51 de novo mPC patients enrolled at two academic centres. CfDNA and matched diagnostic needle biopsies were subjected to deep targeted sequencing across all exons of 73 prostate cancer relevant genes and analyzed independently for somatic alterations.

Results

22 of 31 (71%) ADT-naive patients had detectable ctDNA (fraction range 0.5-70%). A further 20 patients received between 1 and 49 days of ADT prior to cfDNA collection (median 23) and had significantly lower ctDNA fractions than ADT-naive patients (mean 6.0% vs 22.7%; p = 0.009). Although there was no relationship between Gleason score, serum PSA or age at diagnosis and ctDNA fraction, 11 of 13 patients (86%) with lung and/or liver metastases had detectable ctDNA. Excluding one case with hypermutation and mismatch repair deficiency detected only in ctDNA, 83% of non-silent mutations were concurrently identified in both tissue and ctDNA while 9.3% and 7.8% were unique to tissue or ctDNA respectively. 9 patients had truncating mutations and loss of heterozygosity across DNA repair genes BRCA2, ATM, CDK12 or MSH2. No AR gene alterations were detected.

Conclusions

Plasma ctDNA is detected in the majority of patients with de novo mPCa and somatic mutations identified in ctDNA are highly concordant with the matched diagnostic prostate biopsy. Exposure to ADT prior to plasma collection significantly reduces ctDNA detection rates and ctDNA fraction. cfDNA analysis can detect important driver alterations and is complementary to tissue-based analyses.

Legal entity responsible for the study

Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, British Columbia, Canada.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

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Poster Discussion session - Genitourinary tumours, prostate Poster Discussion session

797PD - LATITUDE study: PSA response characteristics and correlation with overall survival (OS) and radiological progression-free survival (rPFS) in patients with metastatic hormone-sensitive prostate cancer (mHSPC) receiving ADT+abiraterone acetate and prednisone (AAP) or placebo (PBO)

Presentation Number
797PD
Lecture Time
09:40 - 09:40
Speakers
  • Nubaki Matsubara (Kashiwa, Chiba, JP)
Location
ICM - Room 14b, ICM München, Munich, Germany
Date
21.10.2018
Time
09:15 - 10:30

Abstract

Background

The randomized, double-blind, active-controlled LATITUDE study found that AAP + ADT significantly improved the primary end points, OS and rPFS vs ADT+PBO in patients with high risk mHSPC. Post hoc analyses were performed to assess correlation of PSA response with OS and rPFS.

Methods

597 men received ADT+AAP and 602 received ADT+PBO. PSA response (confirmed) was based on PCWG2 criteria. Hazard ratios (HR) between treatment arms were determined using Cox proportional-hazards model. Kendall’s tau was used to evaluate correlations.

Results

The overall median (med) baseline PSA was 23.85 ng/mL (range 0.0; 8889.6). Addition of AAP to ADT improved all PSA parameters. Patients receiving AAP were significantly more likely to achieve 50% PSA response (Relative Risk (RR): 1.36) and 90% PSA response (RR: 2.30) vs PBO. Compared to nonresponders, the 50% and 90% PSA response to AAP reduced the risk of death by ≈56% and ≈89% (HR: 0.435 and 0.107, respectively), and by ≈41% and ≈72% (HR: 0.590 and 0.283 respectively) with PBO. A similar effect was noted on rPFS. Further, ADT+AAP demonstrated increasing potential of attaining PSA <0.2 ng/mL at 3, 6 and 12 months (RR: 5.15, 6.35, 6.33, respectively). In the ADT+AAP group, 58% patients reached PSA <0.2 vs 12.8% with PBO. The med time to PSA nadir was 6.4 mo and 3.8 mo in the ADT+AAP and the ADT+PBO groups, respectively. The significantly prolonged med time to PSA nadir in the ADT+AAP group (HR:0.644) was accompanied by a markedly deeper med nadir PSA value (AAP:0.09 ng/mL [range 0.02; 1269.79] vs PBO:2.36 ng/mL [range 0.02; 2254.50]). Lastly, AAP significantly delayed med time to PSA progression as compared to PBO (33.2 mo vs 7.4 mo, respectively; HR: 0.3, p < 0.0001) and the time to PSA progression strongly correlated with rPFS (Kendall’s tau = 0.9211) and OS (Kendall’s tau = 0.666).

Conclusions

Treatment of high-risk mHSPC with ADT+AAP demonstrates a significant depth of PSA response that strongly correlates with long-term outcomes of rPFS and OS.

Clinical trial identification

NCT01715285.

Legal entity responsible for the study

Janssen Research and Development.

Funding

Janssen Research and Development.

Editorial Acknowledgement

Editorial assistance for this poster was provided by Ann C Sherwood, PhD, and editorial assistance was funded by Janssen Research and Development.

Disclosure

K.N. Chi: Institutional funding: Janssen for the study; Grant funding: Astellas, Bayer, Sanofi Janssen; Personal fees: Astellas, Bayer, Sanofi, Essa, Roche. M. Ozguroglu: Honoraria: Janssen, Sanofi. A. Rodriguez Antolin: Consulting services, Expert testimony: Astellas, Bayer, Janssen. S. Feyerabend: Advisory boards: Janssen, Boehringer Ingelheim Pharma, Aventis, Honorarium: Janssen, Travel and accommodation expenses: Aventis. L. Fein: Grant support, Personal fees: Novartis, Pfizer, Roche, Merck, Merck Sharp & Dohme; Grant support: Janssen, AbbVie. B.Y. Alekseev: Personal fees: Janssen, Pfizer, Merck, Roche, Sanofi. A. Protheroe: Consulting, Advisory roles, Travel, accommodations, and expenses: Ipsen, Bayer, Roche, Bristol-Myers Squibb, Merck; Research funding: Merck. G. Sulur, S. Li, P. De Porre, N. Tran, S.D. Mundle: Employee, Stock Owner: Janssen Research & Development. K. Fazazi: Advisory boards; Honoraria: Janssen, Astellas, Sanofi, and Bayer. All other authors have declared no conflicts of interest.

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Poster Discussion session - Genitourinary tumours, prostate Poster Discussion session

Invited Discussant 796PD and 797PD

Lecture Time
09:40 - 09:55
Speakers
  • Joe O'Sullivan (Belfast, GB)
Location
ICM - Room 14b, ICM München, Munich, Germany
Date
21.10.2018
Time
09:15 - 10:30
Poster Discussion session - Genitourinary tumours, prostate Poster Discussion session

Q&A led by Discussant

Lecture Time
09:55 - 10:05
Location
ICM - Room 14b, ICM München, Munich, Germany
Date
21.10.2018
Time
09:15 - 10:30
Poster Discussion session - Genitourinary tumours, prostate Poster Discussion session

798PD - In-depth assessment of metastatic prostate cancer with high tumour mutational burden

Presentation Number
798PD
Lecture Time
10:05 - 10:05
Speakers
  • Niven Mehra (Nijmegen, NL)
Location
ICM - Room 14b, ICM München, Munich, Germany
Date
21.10.2018
Time
09:15 - 10:30

Abstract

Background

A comprehensive assessment of biopsies from metastatic prostate cancer (mPCa) patients (pts) may identify a molecular subset of pts susceptible for immune checkpoint (IC) blockade (ICB).

Methods

148 biopsies and germline DNA from 145 mPCa pts were whole genome sequenced (WGS) at an average of 114x and 38x. Tumour mutational (mut) burden (TMB) was defined as number of somatic single nucleotide variants and InDels per Mb of the genome, known mut signatures (Alexandrov, Nature 2013) extracted by non-negative least squares regression as well as recurrent mutations reported in mismatch repair (MMR) pts (Kim, Cell 2013). Selected pts with high TMB were further evaluated for; (a) MMR protein expression; (b) multiplex intratumoural (IT) immune cell phenotyping (VECTRA); (c) multiplex IC expression (VECTRA); (d) 8-color flow cytometry blood immune cell phenotyping, with high TMB pts compared with low TMB pts. Pts receiving anti-PD-1 ICB had additional immune phenotyping at C2, C3, C4 and at progression; 3 pts had post-progression biopsies analyzed.

Results

The median TMB was 2.9 (IQR 2.2 - 3.9); 12 pts (8.3%) had high TMB (>10 mut/Mb). In 11/12 pts with high TMB, corresponding MMR deficiency (MMRd) signatures (6, 15, 20 and 21) were identified. Recurrent mut in MMR genes were detected MSH2/MSH6, MSH3, MLH1; other recurrent mut were in POLE, and frameshift mut enriched (p < 0.001) in genes including TGFBR2, CLOCK, RPL22 and JAK1. Immunohistochemistry confirmed MMRd in 6/6 biopsies and in matched primary tissue in 5/5 evaluable pts. Five pts were referred for germline testing without MMR mut. A trend for increased IT CD3+ cells were seen in MMRd (p = 0.06); no relation was found between TMB and tumour PD-L1 expression. Pts were treated with anti-PD-1 ICB, with PSA>50% decline of 57% of hTMB pts (n = 7), and a significant decline in circulating T-cell populations during ICB, including CD4+PD-1 + (p = 0.02) and CD8+PD-1 + (p = 0.007). Response rate, duration of response, genomic and immune correlates will be presented for pts with low and high TMB.

Conclusions

8% of mPCa pts display a high TMB with recurrent somatic mut in MMR genes and POLE. MMRd appears early in PCa evolution. High TMB pts witness a high response rate to monotherapy anti-PD-1 ICB.

Clinical trial identification

NCT01855477.

Legal entity responsible for the study

Radboud University Medical Center.

Funding

This data and the underlying study have been made possible partly on the basis of the data that Hartwig Medical Foundation and the Center of Personalised Cancer Treatment (CPCT) have made available to the study.

Disclosure

N. Mehra: Advisory board: Janssen; Honoraria: Bayer, Astellas, Janssen, MSD, BMS; Research funding: Astellas, Janssen. M. van der Doelen: Research grant: Bayer, the Netherlands. I. van Oort: Funding: Astellas, Janssen, Sanofi, Bayer. M.J.L. Ligtenberg: Research funds, Consultancy: AstraZeneca. All other authors have declared no conflicts of interest.

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Poster Discussion session - Genitourinary tumours, prostate Poster Discussion session

799PD - Phase I dose-escalation study of fractionated dose 177Lu-PSMA-617 for progressive metastatic castration resistant prostate cancer (mCRPC)

Presentation Number
799PD
Lecture Time
10:05 - 10:05
Speakers
  • Scott T. Tagawa (New York, US)
Location
ICM - Room 14b, ICM München, Munich, Germany
Date
21.10.2018
Time
09:15 - 10:30

Abstract

Background

PSMA is selectively overexpressed in advanced PC with upregulation by androgen receptor (AR) pathway dysregulation; limited expression in other organs. PC is radiosensitive with dose-response data. Dose-fractionation may allow delivery of higher total doses with less radioresistance than doses several weeks to months apart. Small molecule PSMA inhibitor ligands can be successfully radiolabeled and have been used for imaging and treatment, but no dose-escalation study has been performed.

Methods

Progressive mCRPC following at least 1 potent AR-targeted agent (e.g. abi/enza) and docetaxel (or unfit/refuse chemo) without limit of # prior therapies provided adequate organ function, ECOG performance status 0-2, and without preselection for PSMA expression were enrolled. Treatment was a single cycle of fractionated dose 177Lu-PSMA-617 on D1 and D15 starting at 7.4 GBq with planned escalation up to 22.2 GBq in modified 3 + 3 dose-escalation. Primary endpoint is determination of dose limiting toxicity (DLT) and recommended phase 2 dose (RP2D) with secondary efficacy endpoints. Pre- and post-treatment 68Ga-PSMA11 PET/CT and post-treatment 177Lu-PSMA-617 imaging was performed in addition to standard serial CT and bone scans.

Results

29 men with median age 70 (range 56-87), median PSA 98.9 (range 6-2222) were treated. 93% with bone, 25% node, 14% lung, 7% liver, 7% other visceral metastases. 52% with at least 1 chemo, 45% >1 prior potent AR therapy, 17% with Ra223, 10 sip-T, 3% 177Lu-J591. No DLT was seen at any planned dose-level. With follow up ongoing, 41% with >50% PSA decline. Of 14 with paired CTC counts (CellSearch), 64% decreased, 14% stable, 14% increased (with 28.6% undetectable at 12 weeks). Adverse events include 55% xerostomia, 27.6% fatigue, 27.6% nausea, 27.6% thrombocytopenia, 20.7% anemia, 17.2% back pain. All had some PSMA uptake on imaging, with median (range) SUVmax 25 (4-119) bone, 32 (7-111) node, 10 (3-16) visceral.

Conclusions

Dose-escalation of 177Lu-PSMA-617 is safe up to 22.2 GBq per cycle with fractionated dosing, with promising early efficacy and tolerability signals. Enrollment to the phase 2 study at RP2D will provide additional efficacy and toxicity data.

Clinical trial identification

NCT03042468.

Legal entity responsible for the study

Weill Cornell Medical College.

Funding

Weill Cornell Medical College, Prostate Cancer Foundation, National Institutes of Health.

Disclosure

All authors have declared no conflicts of interest.

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Poster Discussion session - Genitourinary tumours, prostate Poster Discussion session

Invited Discussant 798PD and 799PD

Lecture Time
10:05 - 10:20
Speakers
  • Aristotelis Bamias (Athens, GR)
Location
ICM - Room 14b, ICM München, Munich, Germany
Date
21.10.2018
Time
09:15 - 10:30
Poster Discussion session - Genitourinary tumours, prostate Poster Discussion session

Q&A led by Discussant

Lecture Time
10:20 - 10:30
Location
ICM - Room 14b, ICM München, Munich, Germany
Date
21.10.2018
Time
09:15 - 10:30