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515MO - A phase I trial of durvalumab (Durv) in combination with olaparib (Ola) and capivasertib (Cap) in patients (pts) with advanced or metastatic cancers (Ca) (MEDIPAC)
- Joline S. Lim (Singapore, Singapore)
Abstract
Background
Tumor-specific homologous recombination (HR) DNA defects and the phosphatidylinositol 3-kinase (PI3K)-AKT pathway are commonly implicated in tumorigenesis, and preclinical studies have shown synergistic effects of poly (ADP-ribose) polymerase (PARP) with PI3K-AKT inhibitors. Both pathways modulate the tumor immune microenvironment by regulation of tumor-infiltrating lymphocytes and reduction of Treg cells. We hypothesized that triplet combination of immunotherapy with PARP and PI3K-AKT pathway inhibition is tolerable and may demonstrate activity in pts with relevant pathway defects.
Methods
We investigated the safety and tolerability, pharmacodynamics (PD) and antitumor activity of Durv+Ola, with escalating doses of Cap. Pts were enrolled in 3+3 dose escalation design. Durv and Ola were dosed at standard doses of 1500mg once 4-weekly and 300mg BD continuous dosing respectively. Cap was dosed intermittently (4 days on, 3 days off) with 2 week run-in prior to triplet therapy, at dose levels (DL) 1,2 and 3 of 160mg, 200mg and 320mg BD respectively. PD studies included analyses of plasma (n=18) and paired tumor biopsies (n=12).
Results
22 pts were enrolled, 14 were evaluable; median age 66 (range 36-81), median lines of prior therapy 4 (range 1-13). Dose escalation proceeded through DL1 (n=4, 3 evaluable), DL2 (n=8, 6 evaluable) and DL3 (n=10, 5 evaluable). Treatment was tolerable with mainly G1-2 adverse events (AEs). Most frequent G3/4 AEs were anemia (4/22), hyperglycemia (3/22), and raised lipase (3/22). No DLTs were observed at DL1/2; 1 DLT (G4 hyperglycemia) was observed at DL3. 2 pts had dose reductions (DR) at DL3 for Cap due to G3 hyperglycemia, 3 pts required DR for Ola due to G3 anemia (1 at DL1, 2 at DL2). Treg downregulation was associated with >20% decrease in tumor size by RECIST 1.1 in 1 pt each at DL2 and DL3. 1 pt with
Conclusions
Triplet Cap+Ola+Durv is tolerable with evidence of PD and antitumor activity. Dose expansion at cap 200mg and 320mg OD are ongoing.
Clinical trial identification
NCT03772561.
Editorial acknowledgement
NA
Legal entity responsible for the study
National University Hospital.
Funding
National Medical Research Council Singapore, AstraZeneca.
Disclosure
J.S. Lim: Financial Interests, Personal, Advisory Board: Pfizer; Financial Interests, Personal, Advisory Board: Novartis; Financial Interests, Personal, Advisory Board: Astrazeneca; Financial Interests, Personal, Advisory Board: DKSH; Financial Interests, Personal, Invited Speaker: DKSH; Financial Interests, Personal, Invited Speaker: Roche; Financial Interests, Personal, Invited Speaker: Pierre Fabre; Financial Interests, Personal, Invited Speaker: Astra Zeneca; Financial Interests, Institutional, Invited Speaker: Synthon Pharmaceuticals; Financial Interests, Institutional, Funding: CTI biopharma; Financial Interests, Institutional, Invited Speaker: Daiichi; Financial Interests, Institutional, Invited Speaker: Taiho Pharmaceuticals. R. Sundar: Financial Interests, Personal, Invited Speaker: AstraZeneca; Financial Interests, Personal, Advisory Board: Bayer; Financial Interests, Personal, Invited Speaker: BMS; Financial Interests, Personal, Advisory Board: BMS; Financial Interests, Personal, Advisory Board: Eisai; Financial Interests, Personal, Invited Speaker: Eli Lilly; Financial Interests, Personal, Advisory Board: Merck; Financial Interests, Personal, Invited Speaker: MSD; Financial Interests, Personal, Advisory Board: MSD; Financial Interests, Personal, Advisory Board: Novartis; Financial Interests, Personal, Invited Speaker: Roche; Financial Interests, Personal, Invited Speaker: Taiho; Financial Interests, Personal, Advisory Board: Taiho; Non-Financial Interests, Institutional, Principal Investigator: MSD; Non-Financial Interests, Institutional, Advisory Role: Paxman Coolers. A. Wong: Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Personal, Advisory Board: Pfizer; Financial Interests, Personal, Other, Travel: Eisai; Non-Financial Interests, Institutional, Research Grant: Ostuka. R. Soo: Financial Interests, Personal, Advisory Board: Amgen; Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Personal, Advisory Board: Bayer; Financial Interests, Personal, Advisory Board: BMS; Financial Interests, Personal, Advisory Board: Boehringer Ingelheim; Financial Interests, Personal, Advisory Board: Eli Lilly; Financial Interests, Personal, Advisory Board: Merck; Financial Interests, Personal, Advisory Board: Novartis; Financial Interests, Personal, Advisory Board: Roche; Financial Interests, Personal, Advisory Board: Taiho; Financial Interests, Personal, Advisory Board: Yuhan; Financial Interests, Institutional, Research Grant: AstraZeneca; Financial Interests, Institutional, Research Grant: Boehringer Ingelheim. S.C. Lee: Financial Interests, Personal, Advisory Board: Pfizer; Financial Interests, Personal, Invited Speaker: Pfizer; Financial Interests, Personal, Advisory Board: Eli Lilly; Financial Interests, Personal, Invited Speaker: Eli Lilly; Financial Interests, Personal, Invited Speaker: AstraZeneca; Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Personal, Invited Speaker: Roche; Financial Interests, Personal, Advisory Board: Roche; Financial Interests, Personal, Invited Speaker: ACT genomics; Financial Interests, Personal, Advisory Board: ACT genomics; Non-Financial Interests, Institutional, Principal Investigator, Drug support: Eisai; Non-Financial Interests, Institutional, Principal Investigator, Drug support: Taiho; Non-Financial Interests, Institutional, Principal Investigator, Drug support: Pfizer; Non-Financial Interests, Institutional, Principal Investigator, Drug support: Karyopharm; Financial Interests, Personal, Other, Conference travel: Amgen; Financial Interests, Personal, Other, Conference travel: Pfizer; Financial Interests, Personal, Other, Conference travel: Novartis; Financial Interests, Personal, Other, Conference travel: Roche; Financial Interests, Personal, Other, Conference travel: ACT genomics. B.C. Goh: Financial Interests, Personal, Advisory Role: Adagene; Financial Interests, Institutional, Advisory Board: AstraZeneca; Financial Interests, Institutional, Advisory Board: Bayer; Financial Interests, Institutional, Invited Speaker: MSD; Financial Interests, Personal, Stocks/Shares: Gilead Sciences; Financial Interests, Personal, Stocks/Shares: Moderna; Non-Financial Interests, Institutional, Other, Pharmaceutical suppoer for investigator initiated trial: BMS; Non-Financial Interests, Institutional, Research Grant: MSD; Non-Financial Interests, Institutional, Other, Pharmaceutical suppoer for investigator initiated trial: Taiho. R. Dent: Financial Interests, Personal, Advisory Board, Ad board/speaker: AstraZeneca; Financial Interests, Personal, Advisory Board, Ad board/speaker: Eisai; Financial Interests, Personal, Advisory Board, Ad board/speaker: MSD; Financial Interests, Personal, Advisory Board, Ad board/speaker: Norvatis; Financial Interests, Personal, Advisory Board, Ad board/speaker: Pfizer; Financial Interests, Personal, Advisory Board, Ad board/speaker: Roche; Financial Interests, Personal, Other, Travel, accomodation and expenses: Eisai; Financial Interests, Personal, Other, Travel, accomodation and expenses: MSD; Financial Interests, Personal, Other, Travel, accomodation and expenses: Pfizer; Financial Interests, Personal, Other, Travel, accomodation and expenses: Roche. G. Schiavon: Financial Interests, Personal, Other, Emplyee: AstraZeneca. A. Foxley: Financial Interests, Personal, Other, Employee: AstraZeneca. D.S. Tan: Financial Interests, Personal, Invited Speaker: AstraZeneca; Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Personal, Advisory Board: Bayer; Financial Interests, Personal, Advisory Board: Eisai; Financial Interests, Personal, Invited Speaker: Eisai; Financial Interests, Personal, Advisory Board: Genmab; Financial Interests, Personal, Invited Speaker: Merck Serono; Financial Interests, Personal, Invited Speaker: MSD; Financial Interests, Personal, Advisory Board: MSD; Financial Interests, Personal, Advisory Board: Roche; Financial Interests, Personal, Invited Speaker: Roche; Financial Interests, Personal, Stocks/Shares: Asian Microbiome Library; Financial Interests, Institutional, Principal Investigator: AstraZeneca; Financial Interests, Institutional, Research Grant: AstraZeneca; Financial Interests, Institutional, Principal Investigator: Bayer; Financial Interests, Institutional, Research Grant: Bayer; Financial Interests, Institutional, Principal Investigator: Bergen Bio; Financial Interests, Institutional, Principal Investigator: Byondis B.V; Financial Interests, Institutional, Research Grant: Karyopharm Therapeutics; Financial Interests, Institutional, Research Grant: Roche; Financial Interests, Institutional, Principal Investigator: Zeria Pharmaceutical; Non-Financial Interests, Institutional, Product Samples, Research study: AstraZeneca; Non-Financial Interests, Institutional, Product Samples, Research study: Eisai; Non-Financial Interests, Institutional, Product Samples, Research study: MSD. All other authors have declared no conflicts of interest.
516MO - Phase I/II study of eprenetapopt (APR-246) in combination with pembrolizumab in patients with solid tumor malignancies
- Haeseong Park (St. Louis, MO, United States of America)
Abstract
Background
Eprenetapopt is a small molecule that stabilizes the active form of p53 and increases oxidative stress, resulting in tumor cell apoptosis and ferroptosis and alterations in the tumor microenvironment including immune modulation. In preclinical models, eprenetapopt in combination with anti-PD1 therapy significantly improved tumor growth control and survival
Methods
A safety lead-in with a 3+3 dose de-escalation design for patients (pts) with advanced solid tumors with known tumor
Results
As of April 7, 2021, 20 pts have been enrolled in the study (6 in the safety cohort and 14 in the expansion cohorts: 2 GC, 2 UC, 10 NSCLC) with 18 pts having at least one
Conclusions
The combination of eprenetapopt and pembrolizumab is safe and tolerable. Early signals of anti-tumor activity are observed. The expansion cohorts of the trial continue to enroll.
Clinical trial identification
NCT04383938.
Legal entity responsible for the study
Aprea Therapeutics.
Funding
Aprea Therapeutics.
Disclosure
H. Park: Financial Interests, Institutional, Sponsor/Funding: Aprea Therapeutics. X. Gao: Financial Interests, Personal, Advisory Board: Exilixis. D. Hickman: Financial Interests, Personal and Institutional, Full or part-time Employment: Aprea Therapeutcs. P. Gallacher: Financial Interests, Personal and Institutional, Full or part-time Employment: Aprea Therapeutcs. E. Attar: Financial Interests, Personal and Institutional, Full or part-time Employment: Aprea. All other authors have declared no conflicts of interest.
Discussion 515MO and 516MO
- Aung Naing (Houston, TX, United States of America)
517MO - Phase I study of the porcupine (PORCN) inhibitor RXC004 in patients with advanced solid tumours
- Natalie Cook (Manchester, United Kingdom)
Abstract
Background
Dysregulated Wnt signalling drives several cancers through effects on proliferation, fibrosis and immune evasion. RXC004 is a novel small molecule inhibitor of the protein-serine O-palmitoyltransferase, PORCN, which is required for post-translational modification of Wnt ligands and downstream signaling. RXC004 has potential for monotherapy efficacy in Wnt pathway activated tumours: ∼5% pancreatic and ∼ 8% microsatellite stable colorectal (CRC) cancers with RNF-43 mutations or R-Spondin fusions, and thymus and biliary tract (BTC) cancers with high Wnt ligand activity.
Methods
This open label, 3+3 dose escalation study was one module of a multi-modular adaptive design protocol (NCT03447470). Following a single dose with a 7-day washout, patients received RXC004 once daily in 21-day cycles. The primary objectives were to assess safety and tolerability and define a recommended phase 2 dose of RXC004. Secondary objectives were PK and RECIST response. Pharmacodynamic markers included skin Wnt pathway (Axin2) suppression.
Results
Between 05/02/2018 and 21/06/2021, 25 patients with advanced cancers received RXC004. The first patient, who received 10mg daily, discontinued due to diarrhoea and an asymptomatic clavicle fracture was found on follow up. The half-life (T1/2) and exposure were higher than predicted from preclinical models. The study was paused and restarted at 0.5mg. Subsequently, 1mg, 1.5mg, 2mg and 3mg doses were evaluated. Patients received denosumab 120 mg s.c monthly to prevent bone adverse events [AEs]. For doses <3mg, the most common treatment related AEs were fatigue, nausea, dysgeusia, vomiting and anorexia. No grade 4/5 AEs or bone fragility events were reported. Exposure was dose proportional and median T1/2 was 14.5h. Exposures above the preclinical model IC50 were observed at all doses, as was Axin2 suppression. Five patients, all with Wnt pathway activated tumours [2 BTC, 1 Thymus, 1 mutRNF43 CRC and 1 RSPO fusion CRC] had stable disease, in one case for up to 26 weeks.
Conclusions
In patients with unselected cancers, RXC004 was safe and tolerated at doses up to 2mg/day, supporting phase 2 development in selected patients with Wnt pathway activated tumours. Studies will open in 2021.
Clinical trial identification
EudraCT 2017-000720-98.
Legal entity responsible for the study
Redx Pharma Plc.
Funding
Redx Pharma Plc.
Disclosure
N. Cook: Financial Interests, Personal and Institutional, Advisory Board: Redx Pharma; Financial Interests, Personal, Advisory Board: Roche; Financial Interests, Institutional, Research Grant, research finding: AstraZeneca, Orion, F. Hoffmann-La Roche Ltd, Taiho, GSK, Novartis, Starpharma, Bayer, Eisai, UCB, RedX Pharmaceuticals, Stemline Therapeutics, Boehringer Ingelheim, Merck, Tarveda Therapeutics.S. Blagden: Financial Interests, Institutional, Research Grant, Research funding: Nucana PLC, Sierra Oncology, Astex, Incyte, Tesaro, Redx, MSD, Roche, UCB.; Financial Interests, Personal, Advisory Role, Consulting: Ellipses, Amphista; Financial Interests, Personal, Member of the Board of Directors, Director: RNA Guardian Ltd. D. Sarker: Financial Interests, Personal, Advisory Board: Novartis, Ipsen, Surface Oncology and Eisai; Financial Interests, Personal, Invited Speaker: MSD, Pfizer, Ipsen, Bayer, AstraZeneca and Eisai; Financial Interests, Personal, Funding, Travel payments: Ipsen, Eisai, Bayer and MiNA Therapeutics. A. Greystoke: Financial Interests, Institutional, Research Grant, Research funding: AstraZeneca; Financial Interests, Personal and Institutional, Invited Speaker: AstraZeneca, Amgen, Boehringer-Ingelheim, Bristol-Myers Squibb, Janssen/ J and J, MSD, Novartis, Pfizer, Lilly, Takeda and Roche. L. Goodwin: Financial Interests, Personal, Full or part-time Employment: Redx Pharma. C. Phillips: Financial Interests, Personal, Full or part-time Employment: Redx Pharma. J. Robertson: Financial Interests, Personal, Full or part-time Employment: Redx Pharma. A. Saunders: Financial Interests, Personal, Full or part-time Employment: Redx Pharma. C. Tilston: Financial Interests, Personal, Full or part-time Employment: Redx Pharma. R. Plummer: Financial Interests, Personal and Institutional, Advisory Board: Pierre Faber, Genmab , Bayer, Octimet, Clovis Oncology, Novartis, Karus Therapeutics, Biosceptre, BMS Sanofi Aventis, Ellipses, CV6 Therapeutics, Cybrexa; Financial Interests, Personal, Invited Speaker: AstraZeneca, Novartis, Bayer, Tesaro BMS and Expert Medical Events. All other authors have declared no conflicts of interest.
518MO - Tolerability and preliminary clinical activity of SY-5609, a highly potent and selective oral CDK7 inhibitor, in patients with advanced solid tumors
- Manish Sharma (Grand Rapids, AL, United States of America)
Abstract
Background
SY-5609 is a highly potent inhibitor of CDK7, a key regulator of cell cycle progression and transcription. Initial phase 1 results of SY-5609 in patients (pts) with advanced solid tumors reported proof of mechanism with dose-dependent effects on a pharmacodynamic (PD) gene expression marker
Methods
Doses were escalated (ongoing) above the MTD for continuous dosing in 3 schedules, each with 4-week cycles: 1) once daily (QD) dosing 5 days/week (d/wk), 2) twice daily (BID) dosing 5 d/wk, and 3) QD dosing 7 d/wk every other wk. Select cohorts were expanded to evaluate single agent SY-5609 in specific pt populations and a combination with fulvestrant in hormone receptor positive breast cancer pts. Evaluations included: safety per CTCAE v5.0; clinical activity per RECIST v1.1, tumor markers, and clinical evaluations; and PD marker
Results
As of 3/26/21, 51 pts enrolled, including 9 +fulvestrant. Recently, both QD intermittent dosing schedules cleared dose limiting toxicity (DLT) evaluations at 4 mg/d and 5 mg/d, with activity evaluations and escalation to higher doses ongoing. Single agent SY-5609 AEs of any causality (≥20%) included nausea, diarrhea, fatigue, decreased appetite, and thrombocytopenia; majority were low grade (1/2) and reversible. 30% (11/37) of response-evaluable pts had stable disease (SD) as best response. 6 SD pts had tumor reductions of 8.7%-18.1%, with median 198 d (range: 55-273) on treatment. 1 PDAC pt with prolonged SD (>8 months [ongoing]) had a 72% reduction of CA19-9 (5723 to 1609 U/mL), and 1 ovarian cancer pt had an 84% reduction of CA-125 (1950 to 308 U/mL). Dose dependent
Conclusions
Intermittent dosing of SY-5609 is tolerable above the MTD for continuous dosing with evidence of dose dependent PD effects observed. Early evidence of clinical activity, with durable SD and reduction in tumor size and markers, supports continued dose escalation with intermittent dosing.
Clinical trial identification
NCT04247126; first posted January 29, 2020.
Legal entity responsible for the study
Syros Pharmaceuticals, Inc.
Funding
Syros Pharmaceuticals, Inc.
Disclosure
M. Sharma: Financial Interests, Institutional, Principal Investigator: Alexo; Financial Interests, Institutional, Principal Investigator: Alpine; Financial Interests, Institutional, Principal Investigator: Amgen; Financial Interests, Institutional, Principal Investigator: Apexian; Financial Interests, Institutional, Principal Investigator: Arrys; Financial Interests, Institutional, Principal Investigator: Asana; Financial Interests, Institutional, Principal Investigator: Ascentage; Financial Interests, Institutional, Principal Investigator: AstraZeneca; Financial Interests, Institutional, Principal Investigator: Beigene; Financial Interests, Institutional, Principal Investigator: Bristol-Myers Squibb; Financial Interests, Institutional, Principal Investigator: Bolt; Financial Interests, Institutional, Principal Investigator: Cardiff; Financial Interests, Institutional, Principal Investigator: Celgene; Financial Interests, Institutional, Principal Investigator: Compugen; Financial Interests, Institutional, Principal Investigator: Coordination; Financial Interests, Institutional, Principal Investigator: Constellation; Financial Interests, Institutional, Principal Investigator: CytomX; Financial Interests, Institutional, Principal Investigator: eFFECTOR; Financial Interests, Institutional, Principal Investigator: Eli Lilly; Financial Interests, Institutional, Principal Investigator: Epizyme; Financial Interests, Institutional, Principal Investigator: Exelixis; Financial Interests, Institutional, Principal Investigator: Formation Biologics; Financial Interests, Institutional, Principal Investigator: Forty Seven; Financial Interests, Institutional, Principal Investigator: Genmab; Financial Interests, Institutional, Principal Investigator: GlaxoSmithKline; Financial Interests, Institutional, Principal Investigator: Helsinn; Financial Interests, Institutional, Principal Investigator: Ikena; Financial Interests, Institutional, Principal Investigator: Innovent; Financial Interests, Institutional, Principal Investigator: InhibRx; Financial Interests, Institutional, Principal Investigator: Incyte; Financial Interests, Institutional, Principal Investigator: Ipsen; Financial Interests, Institutional, Principal Investigator: Jounce; Financial Interests, Institutional, Principal Investigator: KLUS Pharma; Financial Interests, Institutional, Principal Investigator: Lexicon; Financial Interests, Institutional, Principal Investigator: LOXO; Financial Interests, Institutional, Principal Investigator: Livzon; Financial Interests, Institutional, Principal Investigator: Macrogenics; Financial Interests, Institutional, Principal Investigator: Merck; Financial Interests, Institutional, Principal Investigator: Mersana; Financial Interests, Institutional, Principal Investigator: NGMBio; Financial Interests, Institutional, Principal Investigator: Northern; Financial Interests, Institutional, Principal Investigator: NovoCure; Financial Interests, Institutional, Principal Investigator: Odonate; Financial Interests, Institutional, Principal Investigator: Pfizer; Financial Interests, Institutional, Principal Investigator: PureTech; Financial Interests, Institutional, Principal Investigator: Regeneron; Financial Interests, Institutional, Principal Investigator: Samumed; Financial Interests, Institutional, Principal Investigator: Sapience; Financial Interests, Institutional, Principal Investigator: Seagen; Financial Interests, Institutional, Principal Investigator: Shattuck; Financial Interests, Institutional, Principal Investigator: Symphogen; Financial Interests, Institutional, Principal Investigator: Syros Pharmaceuticals; Financial Interests, Institutional, Principal Investigator: TaiRx; Financial Interests, Institutional, Principal Investigator: Tesaro; Financial Interests, Institutional, Principal Investigator: Treadwell; Financial Interests, Institutional, Principal Investigator: QED. B. Bashir: Financial Interests, Institutional, Research Grant: Boehringer Ingelheim; Financial Interests, Institutional, Research Grant: Bicycle Therapeutics; Financial Interests, Institutional, Research Grant: Ikena Oncology; Financial Interests, Institutional, Principal Investigator: Syros Pharmaceuticals; Financial Interests, Institutional, Research Grant: Kahr Medical. E. Hamilton: Financial Interests, Institutional, Research Grant: OncoMed; Financial Interests, Institutional, Research Grant: Genentech/Roche; Financial Interests, Institutional, Research Grant: Zymeworks; Financial Interests, Institutional, Research Grant: Rgenix; Financial Interests, Institutional, Research Grant: ArQule; Financial Interests, Institutional, Research Grant: Clovis; Financial Interests, Institutional, Research Grant: Silverback Therapeutics; Financial Interests, Institutional, Research Grant: Millennium; Financial Interests, Institutional, Research Grant: Acerta Pharma; Financial Interests, Institutional, Research Grant: Sermonix Pharmaceuticals; Financial Interests, Institutional, Research Grant: Torque; Financial Interests, Institutional, Research Grant: Black Diamond; Financial Interests, Institutional, Research Grant: Karyopharm; Financial Interests, Institutional, Research Grant: Infinity Pharmaceuticals; Financial Interests, Institutional, Research Grant: Curis; Financial Interests, Institutional, Research Grant: Syndax; Financial Interests, Institutional, Research Grant: Novartis; Financial Interests, Institutional, Research Grant: Boehringer Ingelheim; Financial Interests, Institutional, Research Grant: Immunomedics; Financial Interests, Institutional, Research Grant: FujiFilm; Financial Interests, Institutional, Research Grant: Taiho; Financial Interests, Institutional, Research Grant: Deciphera; Financial Interests, Institutional, Research Grant: Fochon; Financial Interests, Institutional, Research Grant: Molecular Templates; Financial Interests, Institutional, Research Grant: Onconova Therapeutics; Financial Interests, Institutional, Research Grant: Dana Farber Cancer Hospital; Financial Interests, Institutional, Research Grant: Hutchinson MediPharma; Financial Interests, Institutional, Research Grant: MedImmune; Financial Interests, Institutional, Research Grant: SeaGen; Financial Interests, Institutional, Research Grant: Puma Biotechnology; Financial Interests, Institutional, Research Grant: Compugen; Financial Interests, Institutional, Research Grant: TapImmune; Financial Interests, Institutional, Research Grant: Lilly; Financial Interests, Institutional, Research Grant: Pfizer; Financial Interests, Institutional, Research Grant: H3 Biomedicine; Financial Interests, Institutional, Research Grant: Takeda; Financial Interests, Institutional, Research Grant: Merus; Financial Interests, Institutional, Research Grant: Regeneron; Financial Interests, Institutional, Research Grant: Arvinas; Financial Interests, Institutional, Research Grant: StemCentRx; Financial Interests, Institutional, Research Grant: Verastem; Financial Interests, Institutional, Research Grant: eFFECTOR Therapeutics; Financial Interests, Institutional, Research Grant: CytomX; Financial Interests, Institutional, Research Grant: InventisBio; Financial Interests, Institutional, Research Grant: Lycera; Financial Interests, Institutional, Research Grant: Mersana; Financial Interests, Institutional, Research Grant: Radius Health; Financial Interests, Institutional, Research Grant: Abbvie; Financial Interests, Institutional, Research Grant: Nucana; Financial Interests, Institutional, Research Grant: Leap Therapeutics; Financial Interests, Institutional, Research Grant: Zenith Epigenetics; Financial Interests, Institutional, Research Grant: Zenith Epigenetics; Financial Interests, Institutional, Research Grant: Harpoon; Financial Interests, Institutional, Research Grant: Orinove; Financial Interests, Institutional, Research Grant: AstraZeneca; Financial Interests, Institutional, Research Grant: Tesaro; Financial Interests, Institutional, Research Grant: Macrogenics; Financial Interests, Institutional, Research Grant: EMD Serono; Financial Interests, Institutional, Research Grant: Daiichi Sankyo; Financial Interests, Institutional, Research Grant: Syros Pharmaceuticals; Financial Interests, Institutional, Research Grant: Sutro; Financial Interests, Institutional, Research Grant: G1 Therapeutics; Financial Interests, Institutional, Research Grant: Merck; Financial Interests, Institutional, Research Grant: PharmaMar; Financial Interests, Institutional, Research Grant: Olema; Financial Interests, Institutional, Research Grant: Polyphor; Financial Interests, Institutional, Research Grant: Immunogen; Financial Interests, Institutional, Research Grant: Plexxicon; Financial Interests, Institutional, Research Grant: Amgen; Financial Interests, Institutional, Research Grant: Akesobio Australia; Financial Interests, Institutional, Research Grant: Shattuck Labs; Financial Interests, Institutional, Advisory Role: Boehringer Ingelheim; Financial Interests, Institutional, Advisory Role: Novartis; Financial Interests, Institutional, Advisory Role: Dantari; Financial Interests, Institutional, Advisory Role: Lilly; Financial Interests, Institutional, Advisory Role: Merck; Financial Interests, Institutional, Advisory Role: Puma Biotechnology; Financial Interests, Institutional, Advisory Role: Silverback Therapeutics; Financial Interests, Institutional, Advisory Role: CytomX; Financial Interests, Institutional, Advisory Role: Pfizer; Financial Interests, Institutional, Advisory Role: Mersana; Financial Interests, Institutional, Advisory Role: Black Diamond; Financial Interests, Institutional, Advisory Role: H3 Biomedicine; Financial Interests, Institutional, Advisory Role: Daiichi Sankyo; Financial Interests, Institutional, Advisory Role: AstraZenica; Financial Interests, Institutional, Advisory Role: Arvinas; Financial Interests, Institutional, Advisory Role: Deciphera Pharmaceuticals; Financial Interests, Institutional, Advisory Role: Eisai; Financial Interests, Institutional, Advisory Role: Seagen; Financial Interests, Institutional, Advisory Role: Genentech/Roche. D. Juric: Financial Interests, Personal, Advisory Board: Eisai; Financial Interests, Personal, Advisory Board: EMD Serono; Financial Interests, Personal, Advisory Board: Genentech; Financial Interests, Personal, Advisory Board: Ibsen; Financial Interests, Personal, Advisory Board: Novartis; Financial Interests, Personal, Advisory Board: Guardant; Financial Interests, Personal, Advisory Board: Petra Pharma; Financial Interests, Personal, Advisory Board: Mapkure; Financial Interests, Personal, Advisory Board: Vibliome Therapeutics; Financial Interests, Personal, Advisory Board: Relay Therapeutics; Financial Interests, Institutional, Funding: Novartis; Financial Interests, Institutional, Funding: Genentech; Financial Interests, Institutional, Funding: EMD Serono; Financial Interests, Institutional, Funding: Eisai; Financial Interests, Institutional, Funding: Takeda; Financial Interests, Institutional, Funding: Placon Therapeutics; Financial Interests, Institutional, Funding: Syros; Financial Interests, Institutional, Funding: Ribon Therapeutics; Financial Interests, Institutional, Funding: Infinity Pharmaceuticals; Financial Interests, Institutional, Funding: InventisBio; Financial Interests, Institutional, Funding: Amgen. K. Papadopoulos: Financial Interests, Personal, Advisory Role: Basilia; Financial Interests, Personal, Advisory Role: Turning Point Therapeutics; Financial Interests, Personal, Advisory Role: Bicycle Therapeutics; Financial Interests, Institutional, Research Grant: Abbvie; Financial Interests, Institutional, Research Grant: MedImmune; Financial Interests, Institutional, Research Grant: Daiichi Sankyo; Financial Interests, Institutional, Research Grant: Regeneron; Financial Interests, Institutional, Research Grant: Amgen; Financial Interests, Institutional, Research Grant: Calithera Biosciences; Financial Interests, Institutional, Research Grant: Incyte; Financial Interests, Institutional, Research Grant: Merck; Financial Interests, Institutional, Research Grant: Peloton Therapeutics; Financial Interests, Institutional, Research Grant: ADC Therapeutics; Financial Interests, Institutional, Research Grant: 3D Medicines; Financial Interests, Institutional, Research Grant: EMD Serono; Financial Interests, Institutional, Research Grant: Syros Pharmaceuticals; Financial Interests, Institutional, Research Grant: Mersana; Financial Interests, Institutional, Research Grant: MabSpace Biosciences; Financial Interests, Institutional, Research Grant: Jounce Therapeutics; Financial Interests, Institutional, Research Grant: Bayer; Financial Interests, Institutional, Research Grant: Anheart; Financial Interests, Institutional, Research Grant: F-star; Financial Interests, Institutional, Research Grant: Linnaeus; Financial Interests, Institutional, Research Grant: Mirati; Financial Interests, Institutional, Research Grant: Tempest Therapeutics; Financial Interests, Institutional, Research Grant: Lilly; Financial Interests, Institutional, Research Grant: Treadwell Therapeutics; Financial Interests, Institutional, Research Grant: Pfizer. D. Richardson: Financial Interests, Personal, Advisory Role: AstraZeneca; Financial Interests, Institutional, Research Grant: AstraZeneca; Financial Interests, Personal, Advisory Role: Genentech/Roche; Financial Interests, Personal, Advisory Role: Deciphera; Financial Interests, Personal, Advisory Role: Mersana; Financial Interests, Personal, Advisory Role: Tesaro/GlaxoSmithKline; Financial Interests, Institutional, Research Grant: Genentech/Roche; Financial Interests, Institutional, Research Grant: Mersana; Financial Interests, Institutional, Research Grant: Tesaro/GlaxoSmithKline; Financial Interests, Institutional, Research Grant: Aravive; Financial Interests, Institutional, Research Grant: ArQule, Inc.; Financial Interests, Institutional, Research Grant: Deciphera; Financial Interests, Institutional, Research Grant: Harpoon Therapeutics; Financial Interests, Institutional, Research Grant: Innovent Biologics; Financial Interests, Institutional, Research Grant: Karyopharm; Financial Interests, Institutional, Research Grant: Merck; Financial Interests, Institutional, Research Grant: Syros Pharmaceuticals; Financial Interests, Institutional, Research Grant: Five Prime Therapeutics; Financial Interests, Institutional, Research Grant: Hookipa Biotech; Financial Interests, Institutional, Research Grant: FujiFilm; Financial Interests, Institutional, Research Grant: Shattuck Labs; Financial Interests, Institutional, Research Grant: Plexxikon. G. Shapiro: Financial Interests, Personal, Advisory Board: Syros Pharmaceuticals; Financial Interests, Personal, Funding: Eli Lilly; Financial Interests, Personal, Funding: Merck KGaA/EMD Serono; Financial Interests, Personal, Funding: Merck; Financial Interests, Personal, Funding: Sierra Oncology; Financial Interests, Personal, Advisory Board: Pfizer; Financial Interests, Personal, Advisory Board: Eli Lilly; Financial Interests, Personal, Advisory Board: G1 Therapeutics; Financial Interests, Personal, Advisory Board: Roche; Financial Interests, Personal, Advisory Board: Merck KGaA/EMD Serono; Financial Interests, Personal, Advisory Board: Sierra Oncology; Financial Interests, Personal, Advisory Board: Bicycle Therapeutics; Financial Interests, Personal, Advisory Board: Fusion Pharmaceuticals; Financial Interests, Personal, Advisory Board: Cybrexa Therapeutics; Financial Interests, Personal, Advisory Board: Astex; Financial Interests, Personal, Advisory Board: Almac; Financial Interests, Personal, Advisory Board: Ipsen; Financial Interests, Personal, Advisory Board: Bayer; Financial Interests, Personal, Advisory Board: Angiex; Financial Interests, Personal, Advisory Board: Daiichi Sankyo; Financial Interests, Personal, Advisory Board: Seattle Genetics; Financial Interests, Personal, Advisory Board: Boehringer Ingelheim; Financial Interests, Personal, Advisory Board: ImmunoMet; Financial Interests, Personal, Advisory Board: Asana; Financial Interests, Personal, Advisory Board: Artios; Financial Interests, Personal, Advisory Board: Atrin; Financial Interests, Personal, Advisory Board: Concarlo Holdings; Financial Interests, Personal, Advisory Board: Zentalis; Financial Interests, Personal, Advisory Board: Cytomx Therapeutics; Financial Interests, Personal, Advisory Board: Blueprint Medicines; Financial Interests, Personal, Other, Patent: Cyclacel Pharmaceuticals; Financial Interests, Personal, Other, Pending Patent: Liam Cornell. G. Hodgson: Financial Interests, Personal, Full or part-time Employment: syros pharmaceuticals; Financial Interests, Personal, Stocks/Shares: syros pharmaceuticals. N. Ke: Financial Interests, Institutional, Full or part-time Employment: Syros Pharmaceuticals. A. D'Ippolito: Financial Interests, Personal, Full or part-time Employment: Syros Pharmaceuticals. S. Henry: Financial Interests, Institutional, Full or part-time Employment: Syros Pharmaceuticals. L. Zhu: Financial Interests, Personal, Stocks/Shares: Syros Pharmaceuticals; Financial Interests, Personal, Full or part-time Employment: Curis, Inc; Financial Interests, Personal, Stocks/Shares: Incyte Incorporated. M. Rosario: Financial Interests, Personal, Full or part-time Employment: syros pharmaceuticals; Financial Interests, Personal, Stocks/Shares: syros pharmaceuticals. H. Jolin: Financial Interests, Personal, Full or part-time Employment, Former: syros pharmaceuticals. D. Roth: Financial Interests, Personal and Institutional, Officer, Employment, Stocks/Shares: Syros Pharmaceuticals. V. Klimek: Financial Interests, Personal, Full or part-time Employment: Syros. C. Madigan: Financial Interests, Personal, Full or part-time Employment: syros pharmaceuticals. M. Kelly: Financial Interests, Personal, Stocks/Shares: Syros Pharmaceuticals Inc.
Discussion 517MO and 518MO
- Richard F. Schlenk (Heidelberg, Germany)
519MO - Concordance analysis of treatment recommendations between central consensus and multidisciplinary tumor boards
- Hidenori Kage (Bunkyo-ku, Japan)
Abstract
Background
In the era of cancer genome medicine, the role of multidisciplinary tumor boards (MTBs) has been growing and, accordingly, the assurance of the quality of MTBs is rapidly needed. Here we present the results of a prospective analysis evaluating the concordance between treatment recommendations by the MTBs and central consensus treatment recommendations.
Methods
The central committee of the study developed 50 simulated cases which included frequently observed genomic alterations selected from The Cancer Genome Atlas database. The central committee then developed a consensus recommendation for all 50 cases, according to the Japanese practice guideline (Naito Y et al., Int J Clin Oncol 26: 233-283; 2021). The MTBs from twelve leading cancer institutes in Japan independently recommended a treatment for all 50 cases in a blinded manner to the consensus recommendations. The primary objective was to estimate the concordance rate which was defined as the proportion of treatment recommendations by MTBs that were concordant to the consensus recommendations. Mixed effects logistic regression model adjusted for institutes as random intercept was applied.
Results
In 600 (=50 cases×12 institutes) treatment recommendations by the MTBs, the adjusted rate of concordance was 62% (95% confidence interval [CI], 54-69%); the concordance rate across the MTBs varied from 50% to 86%. A high concordance was observed in the subgroups of cases with colorectal cancer (83%), ROS1 fusion (100%), and high evidence level A/R (88/100%), whereas a low concordance was seen in cases with cervical cancer (10%), TP53 mutation (16%), and low evidence level C/D/E (30/25/18%). A multivariate analysis revealed that the level of evidence (high [A/B/R] vs low [C/D/E]; odds ratios, 4.4 [95%CI; 1.8-10.8]), and TP53 alteration (yes vs no; 0.06 [0.03-0.10]) were significant factors associated with concordance.
Conclusions
Our results indicate that sharing the information of matched therapy, particularly for that with low evidence level, may be needed to improve the quality of treatment recommendations by MTBs.
Editorial acknowledgement
Brian Quinn, Japan Medical Communication.
Legal entity responsible for the study
Takayuki Yoshino.
Funding
Ministry of Health, Labour and Welfare, Japan.
Disclosure
H. Kage: Financial Interests, Institutional, Funding: Konica Minolta, Inc..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: Guardant; 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, Invited Speaker: Roche; Financial Interests, Personal, Invited Speaker: Taiho; Financial Interests, Personal, Invited Speaker: 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, Writing Engagements: Eisai Pharmaceutical; Financial Interests, Institutional, Writing Engagements: Kyowa Kirin Pharmaceutical; Financial Interests, Institutional, Research Grant: Chugai Pharmaceutical; Financial Interests, Institutional, Research Grant: Nipponshinyaku Pharmaceutical. M. Kanai: Financial Interests, Personal, Writing Engagements: Chugai. H. Kenmotsu: Financial Interests, Personal, Writing Engagements: Chugai Pharmaceutical; Financial Interests, Personal, Writing Engagements: Ono Pharmaceutical; Financial Interests, Personal, Writing Engagements: Boehringer Ingelheim; Financial Interests, Personal, Writing Engagements: Eli Lilly; Financial Interests, Personal, Writing Engagements: Kyowa Hakko Kirin; Financial Interests, Personal, Writing Engagements: Bristol Myers Squibb; Financial Interests, Personal, Writing Engagements: Novartis Pharma; Financial Interests, Personal, Writing Engagements: Daiichi Sankyo; Financial Interests, Personal, Writing Engagements: AstraZeneca; Financial Interests, Personal, Writing Engagements: Pfizer; Financial Interests, Personal, Writing Engagements: Taiho; Financial Interests, Institutional, Research Grant: Chugai Pharmaceutical; Financial Interests, Institutional, Research Grant: Novartis Pharma; Financial Interests, Institutional, Research Grant: Daiichi Sankyo; Financial Interests, Institutional, Research Grant: AstraZeneca. T. Koyama: Financial Interests, Personal, Writing Engagements: Chugai; Financial Interests, Personal, Writing Engagements: Sysmex; Financial Interests, Personal, Research Grant: PACT. D. Sakai: Financial Interests, Personal, Speaker’s Bureau: Chugai Pharmaceutical; Financial Interests, Institutional, Research Grant: Daiichi Sankyo; Financial Interests, Institutional, Research Grant: Eli Lilly; Financial Interests, Institutional, Research Grant: Chugai Pharmaceutical; Financial Interests, Institutional, Research Grant: Yakult Honsha; Financial Interests, Institutional, Research Grant: Ono Pharmaceutical; Financial Interests, Institutional, Research Grant: Astellas Pharmaceutical; Financial Interests, Institutional, Research Grant: Incyte; Financial Interests, Institutional, Research Grant: Taiho Pharmaceutical; Financial Interests, Institutional, Research Grant: Eisai. T. Yamanaka: Financial Interests, Personal, Writing Engagements: AstraZeneca; Financial Interests, Personal, Writing Engagements: Otsuka; Financial Interests, Personal, Writing Engagements: Ono; Financial Interests, Personal, Writing Engagements: Kyowa Kirin; Financial Interests, Personal, Writing Engagements: Taiho; Financial Interests, Personal, Writing Engagements: Takeda; Financial Interests, Personal, Writing Engagements: Chugai; Financial Interests, Personal, Writing Engagements: Boehringer Ingelheim; Financial Interests, Personal, Writing Engagements: Bayer; Financial Interests, Personal, Writing Engagements: Gilead Sciences; Financial Interests, Personal, Writing Engagements: Sanofi; Financial Interests, Personal, Writing Engagements: Merck Serono; Financial Interests, Institutional, Research Grant: Taiho; Financial Interests, Institutional, Research Grant: Boehringer Ingelheim; Financial Interests, Institutional, Research Grant: Ono; Financial Interests, Institutional, Research Grant: Chugai; Financial Interests, Institutional, Research Grant: Takeda; Financial Interests, Institutional, Research Grant: Astellas; Financial Interests, Institutional, Research Grant: Bayer; Financial Interests, Institutional, Research Grant: Daiichi Sankyo; Financial Interests, Institutional, Research Grant: EPS. 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, Writing Engagements: Taiho; Financial Interests, Personal, Writing Engagements: Chugai; Financial Interests, Personal, Writing Engagements: Eli Lilly; Financial Interests, Personal, Writing Engagements: Merck Biopharma; Financial Interests, Personal, Writing Engagements: Bayer; Financial Interests, Personal, Writing Engagements: 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 Sankyo; Financial Interests, Institutional, Research Grant: Sanofi. All other authors have declared no conflicts of interest.
520MO - Using patient-reported outcomes (PROs) in dose-finding oncology trials (DFOT): Results from a global stakeholder survey and the National Cancer Research Institute (NCRI) Consumer Forum
- Julia E. Lai-Kwon (Melbourne, VIC, Australia)
Abstract
Background
Patient-reported adverse events may be a useful adjunct for assessing a drug’s tolerability in DFOT. However, PRO use is limited and the reasons for this are unknown. We conducted a global online stakeholder survey and a survey at the NCRI Consumer Forum to understand attitudes to PROs in DFOT.
Methods
A 35-question survey of clinicians, trial managers, statisticians, funders and regulators of DFOT from hospitals, academia or industry was distributed via professional bodies. Questions examined prior experience of using PROs, benefits/ barriers to PRO use and their potential role in defining tolerable doses. An 8-question survey of the NCRI Consumer Forum explored similar themes with patients and carers.
Results
Strongly agreed/ agreed (n, %) Global survey (n=112) NCRI Consumer forum survey (n=57) PROs should be communicated in real-time to investigators 62 (55.3%) 54 (94.7%) PROs on adverse events (in conjunction with clinician- assessed CTCAE data) should be used to inform dose escalation decisions 61 (54.5%) 57 (100%) PROs on adverse events (in conjunction with clinician- assessed CTCAE data) should be used to inform the maximum tolerated dose 63 (56.3%) Not assessed PROs on adverse events (in conjunction with clinician- assessed CTCAE data) should be used to inform the recommended phase 2 dose 76 (67.9%) 54 (94.7%)
Conclusions
Trialists and consumers reported minimal prior experience using PROs in DFOT but broadly supported their use in defining tolerable doses. Collaboration between key stakeholders and consumers should inform the research agenda in this area. Guidelines are needed to standardise PRO selection, analysis and reporting in DFOT.
Legal entity responsible for the study
The authors.
Funding
All authors are supported by the National Institute for Health Research (NIHR) Biomedical Research Centre at The Royal Marsden NHS Foundation Trust and The Institute of Cancer Research. The views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care. The authors also acknowledge funding from Cancer Research UK and the Experimental Cancer Centre Initiative.
Disclosure
A. Minchom: Financial Interests, Institutional, Advisory Board: Merck; Financial Interests, Institutional, Advisory Board: FARON; Financial Interests, Institutional, Advisory Board: Novartis; Financial Interests, Institutional, Advisory Board: Bayer; Financial Interests, Institutional, Advisory Board: Janssen. C. Yap: Financial Interests, Institutional, Funding: FARON; Financial Interests, Institutional, Funding: Celgene. All other authors have declared no conflicts of interest.
Discussion 519MO and 520MO
- Richard D. Baird (Cambridge, Cambridgeshire, United Kingdom)