Background

Desmoid tumors (DT) are rare, soft-tissue tumors associated with a potentially debilitating burden. Niro—a targeted gamma secretase inhibitor—is the first systemic treatment for DT approved in the US. In the phase 3 DeFi study, niro demonstrated statistically significant and clinically meaningful improvement vs placebo (pbo) in progression-free survival (PFS), objective response rate (ORR), and PROs of pain, DT-specific symptom burden, physical and role functioning, and overall quality of life (QoL). As DT can have an unpredictable disease course, an improvement in PROs during SD is important to assess, especially during systemic therapy.

Methods

DeFi was a global, multicenter, double-blind study to determine the efficacy, safety, and tolerability of niro in adults with progressing DT. Patients were randomized to receive niro (150 mg) or pbo twice-daily taken in continuous 28-day cycles. Primary endpoint was PFS; key secondary endpoints were ORR by RECIST 1.1 and change from baseline in PROs (BPI-SF, GODDESS, and EORTC QLQ-C30) at treatment Cycle 10. Post hoc analyses of PROs were conducted in patients with a BOR of SD (07Apr2022 datacut).

Results

ORR was significantly greater with niro (29/70 [41%]) than pbo (6/72 [8%]; P<0.001). A total of 35/70 (50%) niro-group patients had a BOR of SD vs 55/72 (76%) pbo-group patients. Niro-treated patients with a BOR of SD had significantly greater improvement from baseline in all PROs at Cycle 10 than pbo (Table).

Table: 57MO

Conclusions

In this post hoc analysis of the DeFi study, patients that achieved RECIST SD as BOR had significantly greater improvement with niro than pbo in pain and DT-specific symptom burden, physical and role functioning, and overall QoL. These results suggest that niro can provide clinically meaningful benefits for patients with DT, including those with RECIST SD as best response.

Clinical trial identification

NCT03785964.

Editorial acknowledgement

Writing and editing support was provided by Jacqueline Benjamin (Prescott Medical Communications Group; Chicago, IL), with funding from SpringWorks Therapeutics, Inc.

Legal entity responsible for the study

SpringWorks Therapeutics, Inc.

Funding

SpringWorks Therapeutics, Inc.

Disclosure

S. Stacchiotti: Financial Interests, Personal, Advisory Board: Bayer, Daiichi Sankyo, Ikena, Regeneron, NEC Oncoimmunity AS, Pharma Essentia; Financial Interests, Personal, Other, Travel Coverage to scientific conference: PharmaMar; Financial Interests, Personal, Advisory Board, Advisory board meeting: Agenus; Financial Interests, Personal, Advisory Board, Advisory board meetings: Boehringer Ingelheim; Financial Interests, Personal, Invited Speaker, Lectures: Gentili; Financial Interests, Personal, Advisory Board, Advisory Board: Servier; Financial Interests, Institutional, Invited Speaker: Advenchen, Bayer, Deciphera, Epizyme, Daiichi Sankyo, GSK, Karyopharm, PharmaMar, SpringWorks, Hutchison MediPharma International Inc, Inhibrix, Inhbrix; Financial Interests, Institutional, Funding: Blueprint, Novartis; Financial Interests, Institutional, Other, Co-investigator in clinical study: Boehringer Ingelheim; Non-Financial Interests, Personal, Member of Board of Directors, Secretary: Connective Tissue Oncology Society; Non-Financial Interests, Personal, Advisory Role: Chordoma Foundation, Epithelioid HaemangiondotheliomaFoundation, DesmoidFoundation, Epithelioid Hemangioendothelioma (EHE) Rare Cancer Charity (UK); Non-Financial Interests, Personal, Other, Secretary: EORTC soft tissue and bone sarcoma group; Non-Financial Interests, Personal, Leadership Role, President: Italian Sarcoma Group. S.P. Chawla: Financial Interests, Personal, Stocks/Shares, Own stocks.: Cellestia pharma; Financial Interests, Personal, Stocks/Shares, Stocks: Adi Biopharma; Financial Interests, Personal, Ownership Interest, Owner and stocks: Counterpoint; Financial Interests, Institutional, Invited Speaker, Clinical research: Amgen; Financial Interests, Institutional, Invited Speaker, Research: Adi bio, NK Gene, BMS, Rain Therapeutic, Shasqui, Monopar, Ayala, Boehringer Ingelheim; Financial Interests, Personal, Invited Speaker, Research: Rain Therapeutic, Molleculin. R. Chugh: Financial Interests, Personal, Funding: SpringWorks Therapeutics, Inc, Ayala, AADi, AstraZeneca, Astex, Cogent, Advenchen, Inhibrx, Epizyme, Pfizer, Plexxikon, Mundipharma, GSK, Qilu Puget Sound, Janssen, Cornerstone, Kronos Bio, PTC Therapeutics; Financial Interests, Personal, Advisory Board: SpringWorks Therapeutics, Inc, Ipsen pharmaceuticals, Deciphera, Inhibrx, Jazz pharmaceuticals. M. Gounder: Financial Interests, Personal, Other, Honoraria: Flatiron Health, PER, Medscape, Guidepoint Global, touchIME, MedLearning Group; Financial Interests, Personal, Advisory Role: More Health, Daiichi Sankyo, Karyopharm Therapeutics, Epizyme, Bayer, Springworks Therapeutics, Boehringer Ingelheim, TYME, Ayala Pharma, Rain Therapeutics, Regeneron; Financial Interests, Personal, Speaker’s Bureau: Amgen, Karyopharm Therapeutics, Boehringer Ingelheim; Financial Interests, Personal, Royalties: UpToDate; Financial Interests, Institutional, Royalties: GODDESS PRO Desmoid Tumor; Financial Interests, Personal, Other, Travel Accommodations: Epizyme. R. Ratan: Financial Interests, Personal, Advisory Board: SpringWorks Therapeutics; Financial Interests, Institutional, Invited Speaker: Ayala Pharmaceuticals, Springworks Therapeutics, C4 Therapeutics. W.T.A. van der Graaf: Financial Interests, Institutional, Advisory Board: PTC Therapeutics, Agenus, SpringworksTx; Financial Interests, Institutional, Invited Speaker, Clinical study: Springworks, Boehringer Ingelheim; Financial Interests, Institutional, Research Grant, IIS: Lilly; Financial Interests, Institutional, Invited Speaker, Clinical Study: AYALA; Non-Financial Interests, Personal, Member of Board of Directors, President: EORTC; Non-Financial Interests, Personal, Member of Board of Directors: European Cancer Organisation; Non-Financial Interests, Personal, Member of Board of Directors, Chair: Dutch Sarcoma Group, Dutch AYA 'Young and Cancer' Care Network. V. Amoruccio, T. Bell, S. Cho: Financial Interests, Personal, Full or part-time Employment: SpringWorks Therapeutics, Inc. P. Schöffski: Financial Interests, Personal, Invited Speaker, Speaker, Consultant, Advisor: Deciphera, Ellipses Pharma, Transgene, Exelixis, Boehringer Ingelheim, Studiecentrum voor Kernenergie, SQZ Biotechnology, Adcendo, PharmaMar, Merck Healthcare KGaA, Medpace, Cogent, Eisai, Curio Science, LLX Solutions, Servier, Genmab, Biolumina, Sanofi, Regeneron, Moleculin Biotech, Avacta Life Sciences, Amryt Pharma, UCB, Boxer Capital; Financial Interests, Institutional, Funding: CoBioRes NV, Eisai, G1 Therapeutics, PharmaMar, Genmab, Merck, Sartar Therapeutics, ONA Therapeutics, Adcendo. All other authors have declared no conflicts of interest.

Background

In 2019, pexidartinib was US FDA-approsssved (800 mg/day TDD) for TGCT patients with severe morbidity or functional limitations not amenable to improvement with surgery. Per label, dose modifications are recommended in certain scenarios, yet long-term data at dosages <800 mg/day are lacking. We evaluated efficacy and safety of 3 doses in a phase 4 study designed to evaluate pexidartinib discontinuation/rechallenge in patients with TGCT.

Methods

This multicenter, open-label, nonrandomized study (NCT04526704) enrolled adults with TGCT from 4 prior pexidartinib trials (NCT02371369; NCT01004861; NCT02734433; NCT03291288). After the prior trials’ end-of-treatment (EOT) visits, patients could choose to enter the Treatment Continuation Cohort (TCC; same dose as EOT) or Treatment-Free/Re-Treatment Cohort (TF/RTC; discontinue pexidartinib with choice to re-initiate at the investigator’s/patient’s discretion). This secondary analysis studied the proportion of progressive disease (PD) by investigator-assessed RECIST v1.1 and safety of 3 pexidartinib doses (800 mg, 600 mg, 400 mg) utilized in the TCC.

Results

From Oct 2020-Apr 2021, 32 patients enrolled; 21/32 chose the TCC with a median age of 47 (range: 21-78) years, 57% (12/21) were female, and 48% (10/21) had knee tumors. In the TCC, 10 (48%), 6 (29%) and 5 (24%) patients were treated at daily doses of 800 mg, 600 mg, and 400 mg, respectively. Patient characteristics were well-balanced across dose, with a median of 10.8 (range: 4.6-32.6) years since diagnosis and a median of 55.3 (range: 26.7-91.0) months of historical pexidartinib treatment. Four of the 21 patients (19%) discontinued this study early due to AE (n = 1; 800 mg), patient withdrawal (n = 2; 800 mg), or physician decision (n = 1; 400 mg). In an average 22.4±4.4 months of follow-up, no TCC patients showed RECIST PD. 19 TCC patients (10 [100%], 6 [100%], 3 [60%] on 800 mg, 600 mg, and 400 mg, respectively) had TEAEs.

Conclusions

Patients who continued pexidartinib experienced disease control with a manageable safety profile across 3 doses. Further evaluation of long-term pexidartinib activity following dose modification is warranted.

Clinical trial identification

NCT04526704; EudraCT 2020-000192-20.

Editorial acknowledgement

Editorial assistance was provided by Heather Nyce, PhD, of Lumanity Scientific Inc., and was financially supported by Daiichi Sankyo, Inc.

Legal entity responsible for the study

Daiichi Sankyo, Inc.

Funding

Daiichi Sankyo, Inc.

Disclosure

S. Stacchiotti: Financial Interests, Personal, Advisory Role: Aadi, Astex Pharmaceuticals, Bavarian Nordic, Bayer, Boehringer Ingelheim, Daiichi Sankyo, Deciphera, Epizyme, Gentili, GSK, Ikena, Maxivax, Novartis, PharmaMar, RainThera, and Servier; and institutional and financial interests from Advenchen, Bayer, Bo. A.J. Wagner: Financial Interests, Personal, Other, Consultant: Aadi Bioscience, BioAtla, Boehringer Ingelheim, Cogent Biosciences, Daiichi Sankyo, Deciphera, Eli Lilly, InhibRx, Kymera, and Servier; Financial Interests, Personal, Research Grant: Aadi Bioscience, Cogent Biosciences, Daiichi Sankyo, Deciphera, Eli Lilly, Foghorn, Karyopharm Therapeutics, Plexxikon, and Rain Therapeutics. I.C. Carrasco Garcia: Financial Interests, Personal, Advisory Board: PharmaMar; Financial Interests, Personal, Other, Consulting, and travel expenses: PharmaMar. C. Lin: Financial Interests, Personal, Advisory Role: AbbVie, Blueprint Medicines, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi Sankyo, Merck KGaA, Novartis, and PharmaEngine; received honorarium from Boehringer Ingelheim, Daiichi Sankyo, Eli Lilly, Novartis and Roche; Financial Interests, Personal, Other, Travel: BeiGene, Daiichi Sankyo, Eli Lilly, and IMPACT Therapeutics.. C.W. Ryan: Financial Interests, Institutional, Research Grant: Ayala, Bristol Myers Squibb, Daiichi Sankyo, Deciphera, Exelixis, Genentech, Novartis, Karyopharm, Merck, Nektar, Pfizer, Xynomic, Bayer, OSI, PF Argentum IP Holdings, Rain Therapeutics, Shasqi; Financial Interests, Personal, Other, Consulting Fees: Synox, Daiichi Sankyo, AVEO, Exelixis, AstraZeneca, Bristol Myers Squibb; Financial Interests, Personal, Expert Testimony: Pfizer, GSK, and Boehringer Ingelheim. W.D. Tap: Financial Interests, Personal, Other, Standard budget for site participation: Plexxikon; Financial Interests, Personal, Advisory Board: Eli Lilly and EMD Serono, Certis Oncology Solutions and Innova Therapeutics; Financial Interests, Personal, Invited Speaker, Consulting Fees: Eli Lilly and EMD Serono; Financial Interests, Personal, Invited Speaker, Travel: Eli Lilly and EMD Serono; Financial Interests, Personal, Other, Personal fees and advisory board: Mundipharma, C4 Therapeutics, Daiichi Sankyo, Blueprint, GSK, and Agios Pharmaceuticals, NanoCarrier and Deciphera; Financial Interests, Personal, Other, Personal fees and consulting: Adcendo, Ayala Pharmaceuticals, Kowa, Servier, and AbMaxBio; Financial Interests, Personal, Stocks/Shares: Certis Oncology Solutions, Atropos Therapeutics.∖. J.C. Trent: Financial Interests, Personal, Advisory Board: Blueprint Medicines, Deciphera, Daiichi Sankyo, Epizyme, Agios, C4 Therapeutics, Bayer, AADI Bioscience, LLC, Foghorn Therapeutics, Boehringer Ingelheim, Cogent Medicine, and Servier. H. Gelderblom: Financial Interests, Institutional, Invited Speaker: Daiichi Sankyo, Deciphera, Novartis, Boehringer Ingelheim, AmMax Bio, Debiopharm, Cytovation, Abbisko. A. Lopez Pousa: Financial Interests, Personal, Other, Site participation in a clinical trial: PharmaMar, Cebiotex, GSK, Eli Lilly, Inmutep and Deciphera. B.A. Van Tine: Financial Interests, Personal, Research Grant: Polaris; Financial Interests, Personal, Other, Consulting Fees: Bayer, Deciphera Pharmaceuticals, Daiichi Sankyo, EcoR1, Advenchen, Putnam, Salarius Pharmaceuticals, Boxer Capital, Acuta Capital Partners, Aadi Biosciences; honoraria for educational talks from Itertion Therapeutics and Total Health Conference; Financial Interests, Personal, Advisory Board: Apexigen, Daiichi Sankyo, Epizyme, Bayer US Medical Affairs, PTC Therapeutics, Aadi Biosciences, Boehringer Ingelheim, Agenus, Regeneron Pharmaceuticals, Advenchen, and Curtis; Financial Interests, Personal, Member of Board of Directors: Polaris; Financial Interests, Personal, Other, Travel: Adaptimmune; Financial Interests, Personal, Other, Patent: Accuronix Therapeutics. M. Rubinacci, K. Tecson, M. Wooddell: Financial Interests, Personal, Full or part-time Employment: Daiichi Sankyo. J. Desai: Financial Interests, Personal, Invited Speaker: Pierre Fabre, Merck KGaA, Novartis, Roche/Genentech, BeiGene, Amgen, AstraZeneca, GSK, Novartis, Pfizer; Financial Interests, Personal, Advisory Board: Bayer, GSK, Boehringer Ingelheim, Roche/Genentech, Pfizer, Amgen, Pierre Fabre, BeiGene; Non-Financial Interests, Personal, Member: ASCO; Non-Financial Interests, Personal, Leadership Role: Australia New Zealand Sarcoma Association. All other authors have declared no conflicts of interest.

Background

Immune checkpoint inhibitor (ICI) effectiveness in unselected STS remains underwhelming but biological rationale suggest that MEK inhibitor combination may enhance response in advanced STS.

Methods

COTESARC is a multicenter, open-label, phase I-II trial evaluating cobimetinib (60 mg orally once daily for days 1 – 21 over 28 days-cycle) plus atezolizumab (840 mg intravenously every 2 weeks) in CG STS, SG STS, malignant peripheral nerve sheath tumors (MPNST), and rhabdomyosarcoma (RMS) cohorts. The progression-free-rate at 16 weeks (PFR-16W) is analysed sequentially every 10 pts per cohort according to a Bayesian approach. The enrolment could be stopped in case of probability for the PFR-16w to be ≤ 30%. Key secondary endpoints are safety, overall response rate (ORR) and progression-free survival (PFS).

Results

Baseline characteristics and main efficacy outcomes are presented for CG and SG cohorts in the table. Unexpected grade 3 myocarditis incidence (n=3/20) was reported. Efficacy outcomes are detailed in the table. With a median follow-up of 18.6 months, 3 pts are still under study treatment: 1 undifferentiated pleomorphic sarcoma and 2 SG STS including 1 alveolar soft part sarcoma with impressive response leading to surgical complete resection.

Table: 59MO

Main efficacy outcomes

Conclusions

Cobimetinib + atezolizumab not seems to demonstrate synergic clinical activity and is associated with an unexpected incidence of myocarditis. Yet, some patients benefit from the combination with long lasting response. Enrollment in MPNST and RMS cohorts is ongoing.

Clinical trial identification

NCT04216953.

Legal entity responsible for the study

Centre Léon Bérard.

Funding

Roche.

Disclosure

A. Dufresne: Non-Financial Interests, Personal, Project ssLead, Translational research project: GSK, Adaptimmune; Non-Financial Interests, Personal, Project Lead, Translational research program: Bayer. M. Brahmi: Financial Interests, Personal, Advisory Board: Bayer; Financial Interests, Personal, Invited Speaker: Amgen, PharmaMar, Deciphera. P. Pautier: Financial Interests, Personal, Advisory Board, 2015, 2022: PharmaMar; Financial Interests, Institutional, Advisory Board, 2020: Roche, Clovis; Financial Interests, Institutional, Advisory Board, 2021: AstraZeneca; Financial Interests, Personal, Advisory Board, 2019-2020: AstraZeneca; Financial Interests, Institutional, Advisory Board: GSK; Financial Interests, Personal, Advisory Board, 2018-2019: Roche; Financial Interests, Institutional, Expert Testimony, 2022: MSD; Financial Interests, Personal and Institutional, Research Grant: PharmaMar; Financial Interests, Personal, Research Grant: ONXEO. I.L. Ray-Coquard: Financial Interests, Personal, Advisory Board: Roche, GSK, AstraZeneca, Mersana, Deciphera, Amgen, Oxnea, Merck Sereno, Agenus, Novartis, Macrogenics, Clovis, EQRX, Adaptimmune, Eisai, SUTRO, BMS, Adaptimmune, Daiichi Sankyo; Financial Interests, Institutional, Other, COLIBRI translational research: BMS; Financial Interests, Institutional, Advisory Board, translational research NEOPREMBROV trial: MSD; Non-Financial Interests, Personal, Principal Investigator: PAOLA1; Non-Financial Interests, Personal, Other, President: GINECO. J-Y. Blay: Financial Interests, Institutional, Invited Speaker: MSD, MSD, PharmaMar; Financial Interests, Institutional, Advisory Board: Bayer, GSK, Roche; Financial Interests, Personal, Advisory Board: Deciphera; Financial Interests, Personal, Other, member of the supervisory board. No remunerations in 2021 and 2022.: Innate pharma; Financial Interests, Personal, Member of Board of Directors: Transgene; Financial Interests, Institutional, Funding: MSD, BMS, Deciphera; Financial Interests, Institutional, Research Grant: AstraZeneca, Roche, Bayer, GSK, Novartis, OSE pharma. All other authors have declared no conflicts of interest.

Background

Patients with advanced soft tissue sarcomas (STSs) have very poor prognosis and systemic chemotherapy is the mainstay of therapy. Prostate-specific membrane antigen (PSMA) is highly expressed on the neovasculature of solid tumors, including 20% of STS lesions. PSMA theranostics using Gallium-68 PSMA-11 PET including contrast-enhanced CT (PSMA PET/ceCT) and Lutetium-177 ITG PSMA radioligand therapy (PSMA RLT) could be an interesting alternative for STS patients after standard therapy. Our single center, prospective clinical trial aims to evaluate feasibility and efficacy in advanced heavily treated patients with STS.

Methods

Patients with STS, progressing after standard therapy, ECOG 0-2 and a life expectancy of >3 months and adequate organ function qualify for study inclusion. Patients were screened by PSMA PET/CT and if uptake was relevant (higher than liver) were proposed to receive two standard cycles of 7400 MBq PSMA RLT in a classical six-week interval. Toxicity was noted using CTCAE v5.0 criteria, efficacy was measured by follow-up PSMA/ceCT to measure changes in PSMA uptake and according to RECIST 1.1. Secondary endpoints include dosimetry, progression-free survival (PFS), adverse events (AEs), overall survival (OS) and changes in immunological markers.

Results

Preliminary results show a high frequency of relevant PSMA uptake in sarcoma lesions of STS patients by PSMA PET/ceCT. Patients amenable for PSMA RLT did well tolerate two cycles of PSMA RLT. Efficacy analysis, toxicity and dosimetry data are currently being analyzed and will be presented at the congress.

Conclusions

PSMA theranostics show an unexpected high number PSMA positive in PSMA PET/ceCT in STS patients. The study is ongoing and final results will be presented at the congress. It might be that PSMA RLT could be a viable alternative for STS patients after exhausting standard treatment however larger trials are needed to better understand the real value of this approach in STS patients.

Clinical trial identification

NCT05420727.

Legal entity responsible for the study

Nuclear Medicine CHUV.

Funding

The Alfred and Annemarie von Sick Grant (Zurich, Switzerland) and the Departments of Oncology and Nuclear Medicine & Molecular Imaging, Lausanne University Hospital (Lausanne, Switzerland).

Disclosure

A. Digklia: Financial Interests, Institutional, Invited Speaker: BMS, Roche; Financial Interests, Institutional, Advisory Board: AstraZeneca. S. Peters: Financial Interests, Institutional, Advisory Board: Vaccibody, Takeda, Seattle Genetics, Sanofi, Roche/Genentech, Regeneron, Phosplatin Therapeutics, PharmaMar, Pfizer, Novartis, Mirati, Merck Serono, MSD, Janssen, Incyte, Illumina, IQVIA, GSK, Gilead, Genzyme, Foundation Medicine, F-Star, Eli Lilly, Debiopharm, Daiichi Sankyo, Boehringer Ingelheim, Blueprint Medicines, Biocartis, Bio Invent, BeiGene, Bayer, BMS, AstraZeneca, Arcus, Amgen, AbbVie, iTheos, Novocure; Financial Interests, Institutional, Invited Speaker: Takeda, Sanofi, Roche/Genentech, RTP, Pfizer, PRIME, PER, Novartis, Medscape, MSD, Imedex, Illumina, Fishawack, Eli Lilly, Ecancer, Boehringer Ingelheim, BMS, AstraZeneca, OncologyEducation, RMEI, Mirati; Financial Interests, Personal, Other, Associate Editor Annals of Oncology and Deputy Editor Lung Cancer: Elsevier; Financial Interests, Institutional, Advisory Board, Permanent independent scientific advisor: Hutchmed; Financial Interests, Institutional, Member of Board of Directors, Swiss network of pharmacies: Galenica; Financial Interests, Institutional, Invited Speaker, MERMAID-1: AstraZeneca; Financial Interests, Institutional, Invited Speaker, MERMAID-2, POSEIDON, MYSTIC: AstraZeneca; Financial Interests, Institutional, Invited Speaker, Clinical Trial Steering committee CheckMate 743, CheckMate 73L, CheckMate 331 and 451: BMS; Financial Interests, Institutional, Invited Speaker, RELATIVITY 095: BMS; Financial Interests, Institutional, Invited Speaker, BGB-A317-A1217-301/AdvanTIG-301: BeiGene; Financial Interests, Institutional, Invited Speaker, Clinical Trial Chair ZEAL-1: GSK; Financial Interests, Institutional, Invited Speaker, Clinical Trial steering Committee PEARLS, MK-7684A: MSD; Financial Interests, Institutional, Invited Speaker, Clinical Trial Steering Committee SAPPHIRE: Mirati; Financial Interests, Institutional, Invited Speaker, LAGOON: PharmaMar; Financial Interests, Institutional, Invited Speaker, phase 1/2 trials: Phosplatin Therapeutics; Financial Interests, Institutional, Invited Speaker, Clinical Trial Chair Skyscraper-01; chair ALEX; steering committee BFAST; steering committee BEAT-Meso; steering committee ImPower-030, IMforte: Roche/Genentech; Financial Interests, Institutional, Invited Speaker, Phase 2 Inupadenant with chemo: iTeos; Non-Financial Interests, Personal, Officer, ESMO President 2020-2022: ESMO; Non-Financial Interests, Personal, Officer, Council Member & Scientific Committee Chair: ETOP/IBCSG Partners; Non-Financial Interests, Personal, Officer, Vice-President Lung Group: SAKK; Non-Financial Interests, Personal, Other, Involved in Swiss politics: Swiss Political Activities; Non-Financial Interests, Personal, Officer, President and Council Member: Ballet Béjart Lausanne Foundation; Non-Financial Interests, Personal, Principal Investigator, Involved in academic trials: ETOP / EORTC / SAKK; Non-Financial Interests, Personal, Member: Association of Swiss Physicians FMH (CH), ASCO, AACR, IASLC; Non-Financial Interests, Personal, Leadership Role, ESMO President: ESMO; Non-Financial Interests, Personal, Member, Vice-President Lung Group: SAKK; Non-Financial Interests, Personal, Leadership Role, Vice -President: SAMO; Non-Financial Interests, Personal, Member, Association of Swiss interns and residents: ASMAC/VSAO. G. Coukos: Financial Interests, Institutional, Advisory Board, CHF 2000 were provided to the CHUV but Dr Coukos did not receive any compensation.: Genentech; Financial Interests, Institutional, Advisory Board, CHF 2400 were provided to the CHUV but Dr Coukos did not receive any compensation.: AstraZeneca; Financial Interests, Institutional, Advisory Board, CHF 1500 were provided to the CHUV but Dr Coukos did not receive any compensation: EVIR; Financial Interests, Personal, Royalties, Dr Coukos has patents in the domain of antibodies and vaccines targeting the tumor vasculature as well as technologies related to T-cell expansion and engineering for T-cell therapy. Dr Coukos holds patents around TEM1 antibodies and receives royalties from the University of Pennsylvania regarding technology licensed to Novartis.: Novartis; Financial Interests, Personal, Royalties, Patent description: CAR T cells. Payment through the University of Pennsylvania: Tmunity Therapeutics; Financial Interests, Institutional, Invited Speaker, Patent description: Methods for expansion of lymphocytes.: Tigen Pharma; Financial Interests, Institutional, Research Grant: Boehringer Ingelheim, Roche, BMS, Iovance Therapeutics, Tigen Pharma. All other authors have declared no conflicts of interest.

Background

Uterine leiomyosarcoma (uLMS) is a rare, aggressive gynecologic malignancy affecting 1 in 200,000 women. uLMS frequently recurs within the peritoneal cavity, which may result from tumor rupture or surgical morcellation. Current standard of care includes cytoreductive surgery (CRS) and systemic chemotherapy, although recurrence rates are high. This prospective phase II trial aims to investigate safety and efficacy of heated intraperitoneal chemotherapy (HIPEC) using gemcitabine followed by systemic dacarbazine after optimal CRS.

Methods

Patients with recurrent uLMS in the peritoneum deemed resectable were evaluated for inclusion. Blood was collected for circulating tumor DNA (ctDNA) and correlative studies. Enrolled patients underwent optimal CRS, HIPEC with gemcitabine (1,000 mg/m2 for 60 minutes at 42C), and 6 cycles of systemic dacarbazine. Primary endpoint is progression-free survival; secondary endpoints are safety and quality of life (QOL) outcomes.

Results

To date, 13 patients have been enrolled. Median age is 55 years (range 31-84) and 8 had history of specimen morcellation. Median peritoneal carcinomatosis index (PCI) is 8 (range 5-14), and all patients received complete cytoreduction (CCR 0 or 1). Three women experienced a complication relating to CRS/HIPEC (bladder injury, ureter transection, neutropenia). There were no grade 3 or higher treatment-related adverse events. Median hospital stay is 6 days (range 2-12). Ten patients developed recurrence at median interval of 8 months (range 1-24); all who recurred continued chemotherapy and 8 underwent additional CRS. Twelve patients remain alive with median follow up of 25 months (range 3-31): 8 have no current evidence of disease, and 4 are alive with disease. ctDNA assays were obtained for 10 patients perioperatively and all have correlated with tumor burden and recurrence. QOL scores were stable at 1 month postoperatively, compared to preoperatively.

Conclusions

Preliminary results of our phase II trial suggest that CRS/HIPEC with gemcitabine and adjuvant dacarbazine is safe. Further patient accrual and analysis are needed to evaluate efficacy in preventing peritoneal recurrence.

Clinical trial identification

NCT04727242.

Legal entity responsible for the study

The authors.

Funding

Stanford Cancer Center.

Disclosure

All authors have declared no conflicts of interest.

Background

Disruption of cell cycle arrest and apoptosis by inactivation of p53 is a key tumour survival and proliferation mechanism and can occur via MDM2 amplification. Thus, inhibiting MDM2 may restore p53 activity in TP53 wild-type tumours. Brigimadlin (BI 907828) is a highly potent, oral MDM2–p53 antagonist that has shown promising preclinical antitumour activity. This phase I study is assessing brigimadlin monotherapy in pts with advanced solid tumours, including WDLPS. Here we report safety data in all pts who received brigimadlin on Day 1 of 21-day cycles (q3w) and updated efficacy data in those with WDLPS.

Methods

In phase Ia, pts received escalating doses of brigimadlin and the recommended dose for expansion was defined as 45 mg q3w (LoRusso et al., Cancer Discovery, 2023). In phase Ib (dose expansion), pts were enrolled to Cohort 1 (TP53wt, MDM2-amplified sarcoma) or Cohort 2 (other TP53wt, MDM2-amplified solid tumours). The primary endpoint for phase Ib was progression-free survival (PFS); secondary endpoints included objective response, disease control rate, and grade ≥3 treatment-related adverse events (TRAEs).

Results

As of 7 Nov 2023, 217 pts had been enrolled. Of these, 190 pts received brigimadlin q3w: the median age was 61 years (19–83 years); 52.6% were male; and 55.8%/43.7% had an ECOG performance score of 0/1. Among these 190 pts, 169 (88.9%) had a TRAE, the most common being nausea (69.5%) and fatigue (54.2%). The most common grade ≥3 TRAEs were neutropenia (27.4%) and thrombocytopenia (23.7%). Seventy pts (36.8%) experienced an adverse event that led to dose reduction, and 11 pts (5.8%) discontinued treatment due to an adverse event. Of the 190 pts who received brigimadlin q3w, 31 had MDM2-amplified WDLPS, of whom 20 were response-evaluable: 3/20 pts (15%) had a confirmed partial response and 16/20 (80%) had stable disease, giving a disease control rate of 95% (19/20). The preliminary median PFS was 25.1 months.

Conclusions

Brigimadlin administered q3w demonstrated a manageable safety profile and encouraging preliminary efficacy in pts with advanced, MDM2-amplified WDLPS.

Clinical trial identification

NCT03449381.

Editorial acknowledgement

Medical writing support was provided by Lucy Lettin of Ashfield MedComms, an Inizio company, and funded by Boehringer Ingelheim.

Legal entity responsible for the study

Boehringer Ingelheim.

Funding

Boehringer Ingelheim.

Disclosure

P. Reichardt: Financial Interests, Personal, Full or part-time Employment: Helios Klinikum Berlin-Buch GmbH; Financial Interests, Personal, Advisory Role: Bayer, Novartis, Roche, Deciphera, Mundibiopharma, PharmaMar, Blueprint Medicines, GSK, Boehringer Ingelheim; Financial Interests, Personal, Other: Clinigen, Deciphera, PharmaMar, Boehringer Ingelheim; Non-Financial Interests, Personal, Other: Chairman of the German Sarcoma Foundation. P. Schöffski: Financial Interests, Personal, Advisory Role: Deciphera, Ellipses Pharma, Transgene, Exelixis, Boehringer Ingelheim, Studiecentrum voor Kernenergie (SCK CEN), SQZ Biotechnology, Adcendo, PharmaMar, Merck, Medpace, Cogent Biosciences, Eisai, Curio Science, LLX Solutions, Genmab, Biolumina, Sanofi, Regeneron, Moleculin Biotech, Avacta Life Sciences, Amryt Pharma, UCB, Boxer Capital; Financial Interests, Institutional, Funding: CoBioRes NV, Eisai, G1 Therapeutics, PharmaMar, Genmab, Merck, Sartar Therapeutics, ONA therapeutics, Adcendo. P. Lorusso: Financial Interests, Personal, Advisory Board: AbbVie, Takeda, Agenus, IQVIA, Pfizer, GSK, QED Therapeutics, AstraZeneca, EMD Serono, Kyowa Kirin Pharmaceutical Development, Kineta, Inc., Zentalis Pharmaceuticals, Molecular Templates, ABL Bio, STCube Pharmaceuticals, I-Mab, Seagen, imCheck, Relay Therapeutics, Stemline, Compass BADX, Mekanistic, Mersana Therapeutics, BAKX Therapeutics, Scenic Biotech, Qualigen, NeuroTrials, Actuate Therapeutics, Atreca Development, Cullinan, Quanta Therapeutics, Schrodinger, Boehringer Ingelheim; Financial Interests, Personal, Other: Roche-Genentech, SOTIO, Roivant Sciences, Amgen CodeBreak 202, DrenBio. N. Yamamoto: Financial Interests, Personal, Other: Chugai Pharma, ONO Pharmaceutical, Daiichi Sankyo/UCB Japan, Eisai; Financial Interests, Personal, Advisory Role: Eisai, Takeda, Boehringer Ingelheim, Cimic, Chugai Pharma, Healios, Merck; Financial Interests, Institutional, Funding: Chugai Pharma, Taiho Pharmaceuticals, Eisai, Astellas Pharma, Novartis, Daiichi Sankyo, Lilly Japan, Boehringer Ingelheim, Takeda, Kyowa Hakko Kirin, Bayer, Pfizer, ONO Pharmaceuticals, Janssen, MSD, AbbVie, Bristol Myers Squibb, Merck Serono, GSK, Sumitomo Dainippon, Carna iosciences, Genmad/Seattle Genetics, Shionogi, Toray Industries, Kaken Pharmaceutical, AstraZeneca, CMIC, InvestisBio, Rakuten Medical. V. Moreno Garcia: Financial Interests, Personal, Advisory Board: AstraZeneca, Basilea, Bayer, Bristol Myers Squibb, Janssen; Financial Interests, Personal, Full or part-time Employment: START; Financial Interests, Institutional, Project Lead: Multiple; Financial Interests, Personal, Other: AbbVie, AceaBio, Adaptimmune, ADC Therapeutics, Aduro, Agenus, Amcure, Amgen, Astellas, AstraZeneca, Bayer, BeiGene, BioInvent International AB, Boehringer Ingelheim, Bristol Myers Squibb, Celegene, Daiichi Sankyo, Debiopharm, Eisai, e-Therapeutics, Exelisis, Forma Therapeutics, Genmab, GSK, Harpoon, Hutchinson, Immutep, Incyte, Inovio, Iovance, Janssen, Kyowa Therapeutics, Lilly, Loxo, MedSir, Menarini, Merus, Millennium, MSD, Nanobiotix, Nektar, Novartis, Odonate Therapeutics, Pfizer, PharmaMar, Principia, PsiOxus, Puma, Regeneron, Rigontec, Sanofi, Sierra Oncology, Synthon, Taiho, Takeda, Tesaro, Transgene, Tuming Point Therapeutics, Upshersmith. I. Lugowska: Financial Interests, Personal, Advisory Role: CLININOTR; Non-Financial Interests, Personal, Member of Board of Directors: OECI-EEIG; Financial Interests, Personal, Other: Roche, Boehringer Ingelheim, MSD, Janssen, Bristol Myers Squibb, RyVu, Incyte, Roche/Genetech, ESMO. U. Lauer: Financial Interests, Personal, Advisory Role: Boehringer Ingelheim; Financial Interests, Personal, Research Grant: Boehringer Ingelheim; Financial Interests, Personal, Advisory Board: Novartis, Asgard Therapeutics, Abalos Therapeutics; Financial Interests, Personal, Other: Boehringer Ingelheim. N. Somaiah: Financial Interests, Personal, Advisory Board: Boehringer Ingelheim. C. Hu, H.T. Landsteiner, G. Jayadeva: Financial Interests, Personal, Full or part-time Employment: Boehringer Ingelheim. M. Gounder: Financial Interests, Personal, Other: Flatiron Health, PER, Medscape, Guidepoint Global, touchIME, Med Learning Group, More Health, Research to Practice, Great Debates and Updates, GLG, OncLive/MJH Life Sciences, Epizyme, Desmoid Tumor Research Foundation; Financial Interests, Personal, Advisory Role: Daiichi Sankyo, Karyopharm Therapeutics, Epizyme, Bayer, Springworks Therapeutics, Boehringer Ingelheim, TYME, Rain Therapeutics, Regeneron; Financial Interests, Personal, Advisory Board: Ayala Pharmaceuticals; Financial Interests, Personal, Speaker’s Bureau: Amgen, Amgen, Boehringer Ingelheim; Financial Interests, Personal, Royalties: UpToDate, GODDESS PRO Desmoid Tumor; Non-Financial Interests, Personal, Other: Foundation Medicine, Athenex.