All times are listed in CET (Central European Time).
- Robin L. Jones (London, United Kingdom)
- Judith Bovée (Leiden, Netherlands)
42O - A phase Ia/b, dose-escalation and expansion study evaluating the MDM2–p53 antagonist BI 907828 in patients with solid tumours: Safety and efficacy in patients with dedifferentiated liposarcoma (DDLPS)
- Patrick Schoeffski (Leuven, Belgium)
- Patrick Schoeffski (Leuven, Belgium)
- Noboru Yamamoto (Chuo-ku, Japan)
- Todd Bauer (Chattanooga, United States of America)
- Manish Patel (Fort Myers, United States of America)
- Patricia Lorusso (New Haven, United States of America)
- Mehdi Lahmar (Ingelheim am Rhein, Germany)
- Sara Durland-Busbice (Ridgefield, United States of America)
- Junxian Geng (Ridgefield, United States of America)
- Mrinal Gounder (New York, United States of America)
Abstract
Background
BI 907828, a highly potent, oral mouse double minute-2 (MDM2)–p53 antagonist, has demonstrated preclinical antitumour activity, particularly in TP53 wild-type (TP53wt), MDM2-amplified DDLPS models. This phase I study is evaluating BI 907828 in patients (pts) with advanced solid tumours, including DDLPS. During dose escalation, the selected recommended dose for expansion (RDE) was 45 mg q3w (Gounder et al, ASCO 2021).
Methods
During dose expansion (phase Ib), pts were enrolled to Cohort 1 (TP53wt, MDM2-amplified sarcoma) or Cohort 2 (other TP53wt, MDM2-amplified solid tumours). Here we focus on Cohort 1 pts (all received BI 907828 45 mg q3w). The primary endpoint was progression-free survival (PFS); secondary endpoints included objective response and grade ≥3 treatment-related adverse events (TRAEs). Here, we present preliminary safety and efficacy results in all pts with advanced DDLPS across dose escalation and expansion.
Results
As of July 2022, 107 pts were enrolled; 59 (55.1%) were male, 63/43 (58.9%/40.2%) had ECOG PS 0/1, respectively, and the median number of prior systemic therapies was 2 (range: 0–11). Of these, 39 pts had advanced DDLPS; 30 received the RDE of 45 mg q3w. Of the 39 DDLPS pts, 35 (89.7%) had a TRAE, including 14 (35.9%) with a grade ≥3 TRAE; the most common grade ≥3 TRAEs were thrombocytopenia (n=8), anaemia (n=4) and neutropenia (n=3). Six pts (15.4%) had an AE leading to dose reduction and 2 (5.1%) had an AE leading to discontinuation. At data cut off, 36 of the 39 DDLPS pts were evaluable for response. Five pts (13.9%) achieved a confirmed partial response (all had received BI 907828 45 mg q3w); a further 27 had stable disease, giving a disease control rate of 88.9%. Preliminary median PFS for all pts with DDLPS was 8.1 months (range: 0.8–21.0); 13 pts are ongoing on treatment.
Conclusions
BI 907828 demonstrated preliminary efficacy and a manageable safety profile in heavily pretreated pts with advanced DDLPS. BI 907828 is also being evaluated versus doxorubicin as first-line treatment for pts with advanced DDLPS in the ongoing phase II/III Brightline-1 study (NCT05218499).
Clinical trial identification
NCT03449381.
Editorial acknowledgement
Medical writing support for the development of this abstract, under the direction of the authors, was provided by Jane Saunders, PhD, of Ashfield MedComms, an Inizio Company, and funded by Boehringer Ingelheim.
Legal entity responsible for the study
Boehringer Ingelheim.
Funding
Boehringer Ingelheim.
Disclosure
P. Schoeffski: Financial Interests, Institutional, Research Grant: CoBioRes NV, Eisai, G1 Therapeutics, PharmaMar, Genmab, Merck, Sartar Therapeutics, ONA Therapeutics, Roche, Adcendo; Financial Interests, Personal, Other, Honoraria/advisory role: Blueprint Medicines, Deciphera, Ellipses Pharma, Transgene, Exelixis, Boehringer Ingelheim, SQZ Biotechnology, Adcendo, PharmaMar, Merck Healthcare KGaA, Cogent Biosciences, Servier, Sanofi, Moleculin, Avacta, Amryt, UCB. N. Yamamoto: Financial Interests, Personal, Speaker’s Bureau: Ono, Chugai, Daiichi Sankyo, Eisai; Financial Interests, Institutional, Research Grant: Astellas, Chugai, Eisai, Taiho, BMS, Pfizer, Novartis, Eli Lilly, AbbVie, Daiichi Sankyo, Bayer, Boehringer Ingelheim, Kyowa-Hakko Kirin, Takeda, Ono, Janssen Pharma, MSD, Merck, GSK, Sumitomo Dainippon, Chiome Bioscience, Otsuka, Carna Biosciences, Genmab, Shionogi, Toray, Kaken, AstraZeneca, Cmic; Financial Interests, Personal, Advisory Role: Eisai, Takeda, Otsuka, Boehringer Ingelheim, Cimic, Chugai, Merck, Healios. T. Bauer: Financial Interests, Personal, Speaker’s Bureau: Bayer, Lilly; Financial Interests, Personal, Full or part-time Employment: Tennessee Oncology; Financial Interests, Institutional, Research Grant: Daiichi Sankyo, Incyte, Mirati Therapeutics, MedImmune, AbbVie, AstraZeneca, MabVax, Merck, Lilly, GlaxoSmithKline, Novartis, Pfizer, Genentech/Roche, Immunogen, Immunocore, Roche, Bristol Myers Squibb, Amgen, Moderna Therapeutics, Sanofi, Boehringer Ingelheim, Astellas Pharma, Top Alliance BioScience, Loxo, Janssen, Takeda, Onyx, Foundation Medicine; Financial Interests, Personal, Advisory Role: Pfizer, Bayer, Lilly, Sanofi; Financial Interests, Personal, Other, travel, accommodation, expenses: Pfizer. M. Patel: Financial Interests, Institutional, Research Grant: Acerta Pharma, ADC Therapeutics, Agenus, Aileron Therapeutics, AstraZeneca, BioNTech, Boehringer Ingelheim, Celgene, CicloMed, Clovis Oncology, Cyteir, Daiichi Sankyo, Lilly, Evelo Therapeutics, Genentech/Roche, Gilead Sciences, GlaxoSmithKline, H3 Biomedicine, Hengrui Therapeutics, Hutchison MediPharma, Jacobio, Janssen, KLUS Pharma, Kymab, Loxo, LSK BioPharma, Lycera, Macrogenics, Merck, Millennium, Mirati Therapeutics, Moderna Therapeutics, Pfizer, Prelude Therapeutics, Ribon Therapeutics, Seven, Eight Biopharmaceuticals, Syndax, Taiho Pharmaceutical, Tesaro, TopAlliance BioSciences Inc., Vigeo Therapeutics, ORIC Pharmaceuticals, Artios, Treadwell Therapeutics, MabSpace Biosciences, IgM Biosciences, Puretech, Artios, BioTheryX, Black Diamond Therapeutics, IgM Biosciences, NGM Biopharmaceuticals, Novartis, PureTech, Relay Therapeutics, Samumed, Silicon Therapeutics, TeneoBio, Treadwell Therapeutics, Zymeworks, Olema Oncology, Adagene, Astellas Pharma, NGM Biopharmaceuticals, Accutar Biotech, TeneoBio, Nurix, Novartis, Compugen, Artios, Blueprint Medicines, Bayer, Bicycle Therapeutics, BioTheryX, Cullinan Oncology, Erasca, Inc., Immune-Onc Therapeutics, Immunitas, Jazz Pharmaceuticals, NGM Biopharmaceuticals, ORIC Pharmaceuticals, Pionyr, Revolution Medicines, Ribon Therapeutics, Step Pharma, Syndax, Synthorx; Financial Interests, Personal, Advisory Role: Olema Pharmaceuticals; Financial Interests, Personal, Leadership Role: ION Pharma; Financial Interests, Personal, Other, honoraria: Janssen Oncology; Financial Interests, Personal, Research Grant: Xencor. P. Lorusso: Financial Interests, Personal, Stocks/Shares: BAKX Therapeutics; Financial Interests, Institutional, Research Grant: Genentech; Financial Interests, Personal, Advisory Role: Genentech, CytomX Therapeutics, Roche/Genentech, Halozyme, Five Prime Therapeutics, Agenus, Agios, Cybrexa Therapeutics, Sotio, AbbVie, Genmab, Takeda, Tyme, Iqvia, Trial to Reduce IDDM in the Genetically at Risk (TRIGR), Pfizer, ImmunoMet, Black Diamond Therapeutics, GlaxoSmithKline, QED Therapeutics, AstraZeneca, EMD Serono, Shattuck Labs, Astellas Pharma, Salarius Pharmaceutical, Silverback Therapeutics, Macrogenics, Kyowa Kirin International, Kineta, Zentalis, Molecular Templates, ABL Bio, SK Life Sciences, ST Cube, Bayer, I-Mab, Seattle Genetics, ImCheck therapeutics, Relay Therapeutics, Stemline Therapeutics, Mekanistic Therapeutics, Compass Therapeutics, BAKX Therapeutics, Scenic Biotech, Qualigen Therapeutics, Roivant, Neurotrials Research; Financial Interests, Personal, Other, travel, accommodations, expenses: Genentech; Financial Interests, Personal, Other, honoraria: Five Prime Therapeutics. M. Lahmar: Financial Interests, Personal, Full or part-time Employment: Boehringer Ingelheim. S. Durland-Busbice: Financial Interests, Personal, Full or part-time Employment: Boehringer Ingelheim. J. Geng: Financial Interests, Personal, Full or part-time Employment: Boehringer Ingelheim. M. Gounder: Financial Interests, Personal, Speaker’s Bureau: Amgen, Karyopharm Therapeutics, Boehringer Ingelheim; Financial Interests, Personal, Proprietary Information: UpToDate; Financial Interests, Institutional, Proprietary Information: GODDESS PRO Desmoid Tumor; Financial Interests, Personal, Advisory Role: Daiichi Sankyo, Karyopharm Therapeutics, Epizyme, Bayer, Springworks Therapeutics, Boehringer Ingelheim, Tyme, Ayala Pharmaceuticals, Rain Therapeutics, Regeneron; Financial Interests, Personal, Other, travel, accommodation, expenses: Epizyme; Financial Interests, Personal, Other, other: Desmoid Tumor Research Foundation; Financial Interests, Personal, Other, honoraria: Flatiron Health, PER, Medscape, Guidepoint Global, touchIME, Med Learning Group, MORE Health; Non-Financial Interests, Personal, Other, Uncompensated Relationships: Foundation Medicine, Athenex; Financial Interests, Personal, Other, Open Payments Link: https://openpaymentsdata.cms.gov/physician/459583.
43O - MDM2 inhibitor milademetan: Safety profile and management of adverse events (AEs)
- Chiara Fabbroni (Milan, Italy)
- Chiara Fabbroni (Milan, Italy)
- Robin L. Jones (London, United Kingdom)
- Tammy Linback (Newark, United States of America)
- Elaine Macneilly (Newark, United States of America)
- Feng Xu (Newark, United States of America)
- Laetitia Simeral (Philadelphia, United States of America)
Abstract
Background
Milademetan (RAIN-32) is a small-molecule MDM2 inhibitor being developed for the treatment of MDM2-dependent, TP53-wildtype tumors. In a first-in-human phase I study, milademetan showed promising clinical activity in dedifferentiated liposarcomas (DDLPS). An intermittent schedule (3/14d) was identified to address on-target cytopenic toxicities and recommended for future clinical development. Two other studies of milademetan are in progress: MANTRA, a randomized phase III study of milademetan vs trabectedin in unresectable/metastatic DDLPS with progression on ≥1 prior systemic therapies; and MANTRA-2, a phase II basket study of milademetan in MDM2-amplified TP53-wildtype advanced solid tumors. We present an overview of milademetan safety data from phase I and II studies and guidance on management of key AEs.
Methods
Phase I: Patients with advanced solid tumors received milademetan qd via four schedules (21/28d; 28/28d; 7/28d; 3/14d). MANTRA-2: patients with MDM2-amplified TP53-wildtype solid tumors received milademetan 260 mg qd 3/14d. Management recommendations were based on clinical experience from different centers (n=9).
Results
Milademetan safety is characterized by hematological and gastrointestinal AEs (Table). The optimum schedule was the intermittent dosing (3/14d) schedule. Preliminary phase II data are consistent with phase I findings. No bleeding events were reported. Data are treatment-related AEs. aData cutoff: 26 Oct 2022 b21/28 days; 28/28 days; 7/28 days
Phase I Phase II (MANTRA-2)a Other schedulesb (n=78) 3/14 days 260 mg (n=20) 3/14 days 260 mg (n=15) All grade Grade ≥3 All grade Grade ≥3 All grade Grade ≥3 Hematological, % Thrombocytopenia 67 35 45 15 27 20 Anemia 42 18 20 0 7 0 Neutropenia 29 19 10 5 7 7 Non-hematological, % Nausea 73 3 80 0 20 0 Vomiting 28 3 50 5 27 0 Diarrhea 33 0 25 0 13 0
Conclusions
Milademetan has a well-established safety profile with hematological and gastrointestinal AEs, common MDM2 inhibitor class effects. Antiemetics should be considered as prophylaxis for nausea/vomiting. An intermittent dosing schedule (3/14d) mitigates the risk of myelosuppression and findings from the MANTRA study of this schedule are awaited with interest. Education of healthcare providers, physicians, and patients in the management of these AEs is important for adherence and maximizing the potential benefit of therapy.
Clinical trial identification
NCT01877382 and NCT05012397.
Editorial acknowledgement
Medical writing/editorial assistance was provided by Lee Miller and Harriet Lamb (Miller Medical Communications Ltd.). This work was funded by the study sponsor (Rain Oncology Inc.).
Legal entity responsible for the study
Rain Oncology Inc.
Funding
Rain Oncology Inc.
Disclosure
C. Fabbroni: Financial Interests, Institutional, Funding: Advenchen, Amgen Dompe, Bayer, Epizyme, Eli Lilly, Daiichi Sankyo, GlaxoSmithKline, Karyopharm, Novartis, Pfizer, PharmaMar, SpringWorks Therapeutics, Rain Therapeutics, Boehringer Ingelheim. R.L. Jones: Financial Interests, Institutional, Research Grant: MSD, GSK; Financial Interests, Personal, Other, Consultation fees: Adaptimmune, Astex, Athenex, Bayer, Boehringer Ingelheim, Blueprint, Clinigen, Eisai, Epizyme, Daiichi Sankyo, Deciphera, Immunedesign, Immunicum, Karma Oncology, Lilly, Merck, Mundipharma, PharmaMar, Springworks, SynOx, Tracon, UpToDate. T. Linback, E. MacNeilly, F. Xu: Financial Interests, Personal, Full or part-time Employment: Rain Oncology Inc.; Financial Interests, Personal, Stocks/Shares: Rain Oncology Inc. All other authors have declared no conflicts of interest.
44O - Comparison of clinical outcomes of patients with infantile fibrosarcoma (IFS) treated with larotrectinib in the SCOUT study versus historical cohort: The EPI-VITRAKVI study
- Daniel Orbach (Paris, France)
- Daniel Orbach (Paris, France)
- Lauriane Lemelle (Paris, France)
- Matthieu Carton (Paris, France)
- Soumeya Khadidja Khadir (Loos, France)
- Marion Feuilly (Loos, France)
- Milena Kurtinecz (Whippany, United States of America)
- Christian Vokuhl (Bonn, Germany)
- Ewa Koscielniak (Stuttgart, Germany)
- Gaelle Pierron (Paris, France)
- Monika Sparber-Sauer (Stuttgart, Germany)
Abstract
Background
For patients with infantile fibrosarcoma (IFS), clinical trials have shown pronounced and durable responses to larotrectinib, a TRK kinase inhibitor. The aim of this study was to assess the effectiveness of Larotrectinib over standard of care (SOC) with chemotherapy, by comparing the time to medical treatment failure (next systemic therapy, mutilating surgery, radiation therapy or death due to any cause) between Larotrectinib and SOC.
Methods
Retrospective observational externally-controlled phase IV study. Data of patients with locally advanced or metastatic IFS, in the phase I/II ‘SCOUT’ clinical trial treated with Larotrectinib (NCT02637687) were compared with the historical control cohorts (data of Institut Curie-Paris and CWS-Cooperative Weichteilsarkom Studiengruppe) treated with chemotherapy-based regimen.
Results
Mean (SD) age of 93 included patients (n=51 [Larotrectinib] and n=42 [control]) was 1.4 (2.9) years: Larotrectinib 2.0 (3.5); control 0.7 (1.8). Locally advanced IFS rates were 80.4% (Larotrectinib) and 92.9% (control). Median durations of follow-up were 30.9 (Larotrectinib) and 72.9 months (control). Four Larotrectinib patients (7.8%) reported a medical treatment failure event (new systemic treatment [n=2], mutilating surgery [n=2]) versus 15 (35.7%) in control group (new systemic treatment [n=6], mutilating surgery [n=5], radiation therapy [n=2] and death [n=2]). Time to medical treatment failure was significantly longer in the Larotrectinib group (weighted log-rank test: p=0.0161). Weighted Hazard Ratio stratified by IRS group stage was 0.20 (95%CI: 0.06-0.63; p=0.0060), which corresponds to an 80% lower likelihood of experiencing a medical treatment failure in the Larotrectinib group. These results were confirmed by sensitivity analyses, including exact matching and subgroup analysis for number of lines of treatment.
Conclusions
This is the first study to provide comparative data on Larotrectinib versus SOC in IFS patients. Results indicate that treatment with Larotrectinib reduced the morbidity and the need of aggressive local therapies compared to SOC in children with IFS.
Clinical trial identification
NCT05236257.
Legal entity responsible for the study
Bayer Inc.
Funding
Bayer Inc.
Disclosure
D. Orbach: Financial Interests, Institutional, Advisory Board, French Larotrectinib Transparency Committee: Bayer; Financial Interests, Institutional, Invited Speaker, Larotrectinib: Bayer; Financial Interests, Institutional, Advisory Board, IDMC for an experimental product: Lilly; Financial Interests, Institutional, Expert Testimony: Roche, Eusapharm; Financial Interests, Institutional, Invited Speaker, An independent translational research project conducted by him is partially supported by Bayer. L. Lemelle, M. Carton, G. Pierron: Financial Interests, Institutional, Funding: Bayer. S.K. Khadir, M. Feuilly, M. Kurtinecz: Financial Interests, Personal, Full or part-time Employment: Bayer. M. Sparber-Sauer: Financial Interests, Institutional, Advisory Board: Bayer, Sobi, Roche. All other authors have declared no conflicts of interest.
Invited discussant
- Jean-Yves Blay (Lyon, France)
- Jean-Yves Blay (Lyon, France)
45O - Clonal evolution of dedifferentiated liposarcoma
- TETSUYA SEKITA (Chuo-ku, Japan)
- TETSUYA SEKITA (Chuo-ku, Japan)
- Naofumi Asano (Shinjuku-ku, Japan)
- Takashi Kubo (Chuo-ku, Japan)
- Sachiyo Mitani (Chuo-ku, Japan)
- Naoko Hattori (Chuo-ku, Japan)
- Akihiko Yoshida (Chuo-ku, Japan)
- Eisuke Kobayashi (Chuo-ku, Japan)
- Motokiyo Komiyama (Chuo-ku, Japan)
- Ushijima Toshikazu (Tokyo, Japan)
- Robert Nakayama (Shinjuku-ku, Japan)
- Akira Kawai (Chuo-ku, Japan)
- Masaya Nakamura (Shinjuku-ku, Japan)
- Hitoshi Ichikawa (Chuo-ku, Japan)
Abstract
Background
Dedifferentiated liposarcoma (DDLPS) is an adipogenic sarcoma composed of a high-grade non-lipogenic (dedifferentiated, DD) component and a juxtaposed well-differentiated (WD) component. Amplification of the 12q13-15 region, including the MDM2 and CDK4 genes, is a common feature of both components, and it is generally accepted that the DD component has transitioned from the preexisting WD component, while a clear trigger for dedifferentiation has not been elucidated.
Methods
We performed multi-region genome (whole exome sequencing, WES), epigenome (DNA methylation microarray), and transcriptome (RNA sequencing) analyses on 3 cases of DDLPS (∼10 regions/case).
Results
WES analysis identified an average of 66 genomic alterations (44 somatic mutations and 22 somatic copy number alterations) in the samples. The 12q13-15 amplification was present in all the samples. In 2 of the 3 cases, there were a few (4 and 2) genomic alterations common to all samples, while samples from the same component (WD or DD) shared much more genomic alterations. This result indicated clonal evolution with very early separation into WD and DD components. A phylogenetic tree generated from DNA methylation pattern was consistent with that from the mutation pattern. The DNA methylation pattern of the WD samples was similar to that of normal fat, whereas the DD samples showed case-specific demethylation. RNA sequencing analysis showed case-specific expression patterns of adipogenesis-related genes, some of which correlated with the methylation status of CpG islands.
Conclusions
We report the first multi-region analysis of DDLPS. Our analyses demonstrated very early branching of the WD and DD tumor clones at least in some DDLPS cases. In addition, case-to-case differences in expression and DNA methylation patterns of adipogenesis-related genes suggested that case-specific DNA methylation alterations contributed to dedifferentiation.
Legal entity responsible for the study
The authors.
Funding
AMED (Japan Agency for Medical Research and Development) JSPS (Japan Society for the Promotion of Science).
Disclosure
H. Ichikawa: Financial Interests, Personal, Research Grant: Ono Pharmaceutical Company, Healios Company, Eisai Company, Chugai Pharmaceutical Company. All other authors have declared no conflicts of interest.
46O - Integrated molecular analysis of human dedifferentiated liposarcoma identifies a population of tumoral progenitors vulnerable to TGF beta inhibition
- Sarah Watson (Paris, France)
- Sarah Watson (Paris, France)
- Nadège Gruel (Paris, France)
- Chloé Quignot (Paris, France)
- Julien Vibert (Paris, France)
- Sylvie Bonvalot (Paris, France)
- Sophie El Zein (Paris, France)
- Dimitri Tzanis (Paris, France)
- Sylvain Baulande (Paris, France)
- Odette Mariani (Paris, France)
- Joshua Waterfall (Paris, France)
- Olivier Delattre (Paris, France)
Abstract
Background
Dedifferentiated liposarcomas (DDLPS) are the most frequent high-grade soft tissue sarcoma in adults. Histologically, these tumors are composed of high-grade undifferentiated tumor cells (DD), often showing an abrupt transition from a compartment of well-differentiated adipocytic tumor cells (WD). Tumor cells from both WD and DD compartments are characterized by recurrent MDM2 amplification, but their cellular origin and the molecular mechanisms associated with dedifferentiation are poorly understood.
Methods
We performed an integrated molecular analysis of tumors collected from 11 patients undergoing surgery for primary untreated DDLPS. DDLPS tumors were analyzed by single-cell RNA sequencing (scRNAseq) and bulk RNA sequencing on paired WD and DD samples from the same tumors. Results were validated in vitro and in vivo in an additional cohort of human tumors, patient-derived xenografts and DDLPS cell lines.
Results
Through RNA-sequencing of 102,753 individual cells from 11 primary DDLPS lesions, major cell clusters were identified based on unsupervised clustering of gene expression profiles and canonical markers. They include 31 tumor microenvironment clusters and 11 tumor cell clusters. A cluster of tumor cells from the WD compartment is characterized by signatures of early adipocytic progenitors, previously identified as TGFb-dependent, multipotent stromal progenitors. We show that these cells harbor specifically the truncal genomic alterations of the cancer, with further subclonal alterations identifiable in both WD and DD compartments of DDLPS. Furthermore, these cells have multipotent properties and their differentiation towards the adipocytic lineage is inhibited by TGFb. Treatment of DD tumor cells with TGFb inhibitors restores their adipocytic phenotype in vitro and in vivo.
Conclusions
We provide the first single-cell atlas of human DDLPS tumor and microenvironment and identify a population of adipocytic tumor progenitors at the origin of both WD and DD compartments. This study paves the way for a new model of DDLPS oncogenesis and provides rationale for the development of therapeutic strategies based on TGFb inhibition.
Legal entity responsible for the study
The authors.
Funding
Les Entreprises Contre le Cancer, Cancéropôle Emergence, Fondation ARC.
Disclosure
All authors have declared no conflicts of interest.
Invited discussant
- Eva Wardelmann (Muenster, Germany)
- Eva Wardelmann (Muenster, Germany)
Q&A
- Robin L. Jones (London, United Kingdom)
- Judith Bovée (Leiden, Netherlands)
- Robin L. Jones (London, United Kingdom)
- Judith Bovée (Leiden, Netherlands)