AB010. A phase 1 trial of PRTH-101, a monoclonal antibody targeting discoidin domain receptor 1 (DDR1), alone or in combination with pembrolizumab, for the treatment of thymic malignancies
Clinical Trial in Progress (Original Research)

AB010. A phase 1 trial of PRTH-101, a monoclonal antibody targeting discoidin domain receptor 1 (DDR1), alone or in combination with pembrolizumab, for the treatment of thymic malignancies

Funda Meric-Bernstam1, So Yeon Kim2, Shiraj Sen3, Christopher Nabel4, David Sommerhalder5, Rachel E. Sanborn6, Aparna Parikh4, Julia Moore1, Jordan Berlin7, Patricia LoRusso2, G. Travis Clifton8, Irena Webster8, Amy Mueller8, Thomas Schürpf8, Susan Macdonald8, Joseph P. Eder8, Alex Spira9

1Department of Investigational Cancer Therapeutics, MD Anderson Cancer Center, Houston, TX, USA; 2Department of Medical Oncology and Hematology, Yale Cancer Center, New Haven, CT, USA; 3NEXT Oncology, Dallas, TX, USA; 4Department of Medicine, Massachusetts General Hospital, Boston, MA, USA; 5NEXT Oncology, San Antonio, TX, USA; 6Thoracic Oncology Program and Phase 1 Clinical Trials Program, Earle A. Chiles Research Institute Providence Cancer Institute, Portland, OR, USA; 7Department of Medicine, Vanderbilt-Ingram Cancer Center, Nashville, TN, USA; 8Incendia Therapeutics, Cambridge, MA, USA; 9NEXT Oncology, Arlington, VA, USA

Correspondence to: Susan Macdonald, PhD. Incendia Therapeutics, One Canal Park, Cambridge, MA 02141, USA. Email: sue.macdonald@incendiatx.com.

Background: There are no Food and Drug Administration (FDA)-approved therapies for recurrent/metastatic thymic epithelial cancers (TECs) and current treatments with chemotherapy and immunotherapy leave considerable room for improvement. Discoidin domain receptor 1 (DDR1) is a collagen receptor expressed on tumor epithelial cells. DDR1 binding to collagen surrounding tumor cells results in highly aligned collagen fibers, and exclusion of cluster of differentiation 8 (CD8)+ T cells from the tumor (i.e., immune exclusion), precluding an effective anti-tumor response. High DDR1 expression has been observed in TECs and other epithelial tumor types. Furthermore, published data suggest that high DDR1 expression is associated with poor prognoses and lack of response to immunotherapies. The purpose of this article is to describe the results of PRTH-101 treatment in thymic cancer patients in our ongoing clinical trial.

Methods: PRTH-101 is a humanized monoclonal antibody that blocks the interaction of collagen with the extracellular domain of DDR1; it is being tested in a phase 1 clinical trial (PRTH-101-0001) as a single agent (phase 1a) and in combination with pembrolizumab (phase 1b). PRTH-101 doses up to 1,600 mg have shown no dose-limiting toxicities alone or together with pembrolizumab. Clinical, pharmacokinetic, and target engagement data from 56 patients have informed a recommended phase 2 dose of 1,200 mg, which is being tested in phase 1c, with or without pembrolizumab.

Results: To date, 16 TEC/thymoma patients have been treated with PRTH-101 at doses of 240 to 1,600 mg, 10 of whom have also received pembrolizumab; 14 had previously progressed on immunotherapy. Of seven patients in phase 1a and phase 1b who stayed on trial for more than one cycle, median progression-free survival (mPFS) is >7.7 months (2 ongoing) [>9.8 months mPFS for thymoma (1 ongoing); >6.6 months mPFS for TEC (1 ongoing)]. PFS was observed in patients receiving PRTH-101 alone or with pembrolizumab, irrespective of programmed death-ligand 1 (PD-L1) status. One previously untreated patient with metastatic TEC receiving 1,200 mg PRTH-101 with pembrolizumab, has an ongoing partial response, despite a PD-L1 combined positive score <1%. Six patients (of seven) are ongoing in phase 1c.

Conclusions: DDR1 and PD-L1 expression data, combined with PFS data, suggest that PRTH-101 contributes to or is responsible for observed PFS in these patients. The data support further clinical evaluation of PRTH-101 alone and in combination with pembrolizumab for patients with recurrent/metastatic TEC.

Keywords: PRTH-101; discoidin domain receptor 1 (DDR1); programmed death-ligand 1 (PD-L1); phase 1; pembrolizumab

Acknowledgments

None.

Footnote

Funding: This work was supported by Incendia Therapeutics.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://med.amegroups.com/article/view/10.21037/med-25-ab010/coif). All authors report this work was supported by Incendia Therapeutics. F.M.B. received grants from Jazz Pharmaceuticals, Zymeworks, Aileron Therapeutics, Inc., AstraZeneca, Bayer Healthcare Pharmaceutical, Calithera Biosciences, Inc., Curis, Inc., CytomX Therapeutics, Inc., Daiichi Sankyo Co. Ltd., Debiopharm International, eFFECTOR Therapeutics, Genentech, Inc., Guardant Health, Inc., Klus Pharma, Takeda Pharmaceuticals, Novartis, Puma Biotechnology, Inc. and Taiho Pharmaceutical Co. F.M.B. also received Consulting fees from AstraZeneca Pharmaceuticals, Becton Dickinson, Biocartis NV, Calibr (a division of Scripps Research), Daiichi Sankyo, Dava Oncology, Debiopharm, EcoR1 Capital, eFFECTOR Therapeutics, Elevation Oncology, Exelixis, GT Aperion, Incyte, Jazz Pharmaceuticals, LigaChem Biosciences, LegoChem Biosciences, Lengo Therapeutics, Menarini Group, Molecular Templates, Protai Bio, Ribometrix, SystImmune, Tallac Therapeutics, Tempus, Vir Biotechnology and Zymeworks and received honoraria from Dava Oncology. FMB received support for travel from European Organisation for Research and Treatment of Cancer (EORTC), European Society for Medical Oncology (ESMO), Cholangiocarcinoma Foundation and Dava Oncology. She also participation on Advisory Committee of Cybrexa, go Therapeutics, Guardant Health, Harbinger Health, Illumen Therapeutics, Kivu Biosciences, LOXO-Oncology, Mersana Therapeutics, OnCusp Therapeutics, Sanofi Pharmaceuticals, Seagen, Theratechnologies and Zentalis Pharmaceuticals. SS is staff of NEXT Oncology. CN received grants from Thymic Carcinoma Center (Medical Research Grant SDaulton 001). D.S. received consulting fees from Revolution Medicines, Nimbus Therapeutics, Syneos and Guidepoint, and received honoraria from Ideology Lectures. D.S. is the shareholder of Texas Oncology and NEXT Oncology. He received Institutional Research funding from Abbvie, Acrivon Therapeutics, ADC Therapeutics, Aprea Therapeutics, Ascentage Pharma Group, Astellas, Biomea Fusion, Boehringer Ingelheim, BJ Bioscience, BioNTech, Bristol-Myers Squibb, Compugen, Day One Biopharma, Dicerna/Novo Nordisk, Exelixis, Fate Therapeutics, Gilead Sciences, GlaskoSmithKline, Haihe Pharmaceutical, Iconovir Bio, Immuneering, Impact Therapeutics, Incendia, Kura Oncology, MediLink Therapeutics, Mirati Therapeutics, ModeX Therapeutics, Monopteros Therapeutics, Navire Pharma Inc., Nimbus Therapeutics, NGM Biopharmaceuticals, OBI Pharma, OncoResponse Inc., Pfizer, Revolution Medicines, Step Pharmaceuticals, Symphogen, Tachyon Therapeutics, Teon Therapeutics, Tyligand Bioscience, Vincerx Pharma, Vividion Therapeutics, ZielBio Inc and Zymeworks Inc. DS is staff of NEXT Oncology. R.E.S. received consulting fees from AstraZeneca, Janssen Oncology/Johnson and Johnson, Sanofi Aventis, GlaxoSmithKline, Illumina, G1 Therapeutics, Daiichi Sankyo, Lilly Oncology, Amgen, Gilead Sciences, GE Healthcare, AbbVie, IDEOlogy Health, BeiGene, Inhibrx, Boehringer Ingelheim, Rigel, Pfizer and Natera, and received payment or honoraria from Targeted Oncology, Curio Science, Illumina, OncLive and PRIME Education. R.E.S. also received support for attending meetings and/or travel from HotSpot Therapeutics, and received Funding for Investigator-initiated trial from Merck and AstraZeneca. She also participation on DSMB. A.P. has held Equity in C2i Genomics, Khora, OneCell, XGenomes, Cadex, and Parithera. In the last 36 months, she received consulting fees from Zola, CVS, Phesi, Xilio, 3T Biosciences, Do More Diagnostics, Summit Therapeutics, Pfizer, Regenerson, GSK, Foundation Medicine, Careset, Value Analytics Labs, Naterara, Adroya, Astra Zeneca, Scare, Hookipa, Guardant, Abbvie, Seagen, Mirati, Takeda, PMV, Kahr, Sirtex, Eli Lilly, Merck, Amgen, Delicate, Exact, Caris, BMS, Incyte, Phesi, Neogenomics, J & J, Exact Third Rock Ventures, MPM Capital, and Science For America. She receives fees from Up to Date. She has received travel fees from Karkinos Healthcare. She has received research funding to the Institution from PMV Pharmaceuticals, BMS, Mirati, Erasca, Genentech, Daiichi Sankyo, Syndax, Revolution Medicine and Parthenon. JB received grants from Abbvie, Astellas, Atreca, Bayer, Dragonfly, I-Mab, Lilly, Incyte, EMD Serono, Pfizer, BMS, Tyra, Totus, Sumitomo Dainippon Pharma Oncology, 23 and me, parthenon/Incendia, hibercell, ribosciences, NCI, BMS and Clasp, and received consulting fees from EMD Serono 3/25, 4/25*, Ipsen 5/25*, Merck, Sharp, Dohme, Merus, Bms, Mekanistic, Agenus (pending), Astellas, Amplia, Taiho*, Regeneron 1/25, Beigene 1/25 and ALX Oncology 6/25. J.B. received support for attending meetings and/or travel from Ipsen and EMD Serono, and participation on a Data Safety Monitoring Board or Advisory Board of Astra Zeneca, I-SPY and Novocure. G.T.C. is a former employee of Incendia Therapeutics and may be named as an inventor on a methods-of-use patent for PRTH-101 with Incendia Therapeutics; G.T.C. previously held stock options from Incendia Therapeutics (no longer holds any). A.M. and I.W. are employees of Incendia Therapeutics and have received support for attending meetings as well as stock options from Incendia Therapeutics. T.S., S.M., and J.P.E. are employees of Incendia Therapeutics, have received support for attending meetings and/or travel, hold stock options from Incendia Therapeutics, and may be named as inventors on a methods-of-use patent for PRTH-101 with Incendia Therapeutics. A.S. received grants from LAM Therapeutics, Roche, Astra Zeneca, Boehringer Ingelheim, Astellas Pharma, Incyte, Novartis, AbbVie, Ignyta, Takeda, Macrogenics, CytomX Therapeutics, Astex Pharmaceuticals, Bristol-Meyers Squibb, Loxo, Gritstone, Plexxikon, Amgen, Daiichi Sankyo, ADCT, Janssen Oncology, Rubius, Synthekine, Mersana, Blueprint Medicines, Regeneron, Alkermes, Black Diamond Therapeutics, Nalo Therapeutics, Scorpion Therapeutics, ArriVent Biopharma, Revolution Medicines, Prelude Therapeutics and Lilly, received consulting fees from Incyte, Amgen, Novartis, Mirati Therapeutics, Gritstone Oncology, Jazz Pharmaceuticals, Takeda, Janssen Research & Development, Mersana, Daiichi Sankyo/Astra Zeneca, Regeneron, Lilly, Black Diamond Therapeutics, Sanofi, ArriVent Biopharma, Synthekine, GSK, CRISPR Therapeutics, Revolution Medicines, Astra Zeneca/MedImmune, Merck, Bristol-Meyers Squibb and Blueprint Medicines, and received honoraria from CytomX Therapeutics, Merck, Takeda, Amgen, Janssen Oncology, Novartis, Bristol-Meyers Squibb, Bayer, Prelude Therapeutics, AbbVie and Astellas Pharma. A.S. is staff of NEXT Oncology. The authors have no other conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by Salus IRB (registration numbers IRB00006833, IRBI00006834, IRB00009473, IRB00013027, and IRB00013544), MD Anderson IRB (registration number IRB00000121), Vanderbilt Human Research Protection Program, Health Sciences Committee 3 IRB (registration number IRB00002125), Providence St. Joseph Health IRB (registration numbers IRB00012388, IRB00012541, IRB00012389, IRB00012390, IRB00012391, IRB00012392, IRB00012393, IRB00012882, and IRB00012964), Mass General Brigham IRB (registration numbers IRB00012706 and IRB00012707), and WCG IRB (registration number IRB00000533) and informed consent was obtained from all individual participants.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

doi: 10.21037/med-25-ab010
Cite this abstract as: Meric-Bernstam F, Kim SY, Sen S, Nabel C, Sommerhalder D, Sanborn RE, Parikh A, Moore J, Berlin J, LoRusso P, Clifton GT, Webster I, Mueller A, Schürpf T, Macdonald S, Eder JP, Spira A. AB010. A phase 1 trial of PRTH-101, a monoclonal antibody targeting discoidin domain receptor 1 (DDR1), alone or in combination with pembrolizumab, for the treatment of thymic malignancies. Mediastinum 2025;9:AB010.

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