Brightline-2: A phase IIa/IIb, open-label trial of the MDM2–p53 antagonist BI 907828 in patients with advanced MDM2-amplified, TP53 wild-type biliary tract cancer, pancreatic ductal adenocarcinoma, or other selected solid tumours

Further therapeutic options are urgently required for patients with biliary tract cancer (BTC), pancreatic ductal adenocarcinoma (PDAC), lung adenocarcinoma and bladder cancer, especially following failure of standard treatment. Mouse double minute 2 (MDM2) is amplified in ∼5–6% of cases of BTC, ∼1% of PDAC, ∼4% of lung adenocarcinomas and ∼7% of bladder cancers. MDM2, an E3 ubiquitin ligase, is an endogenous negative regulator of p53. Preclinical and emerging clinical data indicate that blocking MDM2 in TP53 wild-type tumours may be a potential therapeutic strategy. BI 907828 is an MDM2–p53 antagonist that binds to MDM2 and blocks its interaction with p53, thereby restoring p53 function, leading to cell-cycle arrest and apoptosis in TP53 wild-type tumours. In ongoing phase I studies, BI 907828 has shown preliminary activity in selected advanced/metastatic solid tumours. Currently, ten patients with BTC had received BI 907828 ± ezabenlimab (an immune checkpoint inhibitor). Of these patients, five had a partial response (PR) and three had stable disease (SD). Patients with PDAC (n=1; PR), urothelial cancer and lung adenocarcinoma have also been treated and have shown promising outcomes.

Brightline-2 (NCT05512377) is a phase IIa/IIb, open-label, single-arm, multicentre study assessing the efficacy and safety of BI 907828 monotherapy in patients with locally advanced, unresectable, or metastatic MDM2 -amplified, TP53 wild-type BTC (adenocarcinoma histology; Cohort 1; n=∼90), PDAC (Cohort 2; n=∼10), lung adenocarcinoma (Cohort 3; n=∼15) or urothelial bladder cancer (Cohort 4; n=∼15). All patients will receive BI 907828 45 mg orally once every 3 weeks. Key inclusion criteria: ≥18 years; locally advanced/metastatic, histologically confirmed unresectable BTC/PDAC/lung adenocarcinoma/urothelial bladder cancer; progression/intolerance to standard therapies; local test indicating MDM2 amplification or MDM2 copy number ≥8 and TP53 wild type (liquid biopsy not permitted); ≥1 measurable target lesion (RECIST v1.1); and ECOG PS 0/1. Prior treatment with an MDM2–p53 antagonist is not permitted. Treatment will continue until disease progression, unacceptable toxicity, or withdrawal of consent. The primary endpoint is objective response rate (ORR; central independent review; RECIST v1.1). Secondary endpoints are duration of response, progression-free survival, overall survival, disease control, occurrence of adverse events, and patient-reported health-related quality of life. Patient-reported outcomes will be collected at multiple time points via questionnaires: EORTC QLQ-C30; EORTC IL46 (item 168); Patient Global Impression of Severity (PGIS); Patient Global Impression of Change (PGIC); EORTC QLQ-BIL21 (Cohort 1); EORTC QLQ-PAN26 (Cohort 2 only); NSCLC-SAQ (Cohort 3). In phase IIa, an interim futility analysis will be performed after the initial 30 patients in Cohort 1 have either been followed for ≥12 weeks or have discontinued. If the cohort passes the non-binding interim futility boundary (ORR=20%), the study will enter phase IIb, and 60 additional patients will be enrolled onto Cohort 1. Across Cohort 2–4, futility analyses will be performed to assess the efficacy signal before deciding on the next steps. The final primary analysis will be performed after all treated patients have been followed for ≥12 weeks, or until study discontinuation. As of February 2023, 16 patients have been enrolled.

NCT05512377.

Medical writing assistance, funded by Boehringer Ingelheim, was provided by Jim Sinclair, PhD, of Ashfield MedComms, an Inizio Company, during the preparation of this abstract.

Boehringer Ingelheim.

Boehringer Ingelheim.

T. Macarulla: Advisory / Consultancy: Ability Pharmaceuticals SL, AstraZeneca, Basilea Pharma, Baxter, BioLineRX Ltd, Celgene, Eisai, Incyte, Ipsen Bioscience Inc, ; Speaker Bureau / Expert testimony: Janssen, Lilly, ; Research grant / Funding (self): MSD, Novocure, QED Therapeutics, Roche Farma, Sanofi-Aventis, Servier, Zymeworks ; Travel / Accommodation / Expenses: Servier, AstraZeneca, Sanofi, Incyte and MSD. J. Harding: Honoraria (self): HCC Connect, OncLive; Advisory / Consultancy: Adaptimmune, AstraZeneca, Bristol Myers Squibb, Exelexis, Elevar, Eisai, Genoscience (uncompensated), Hepion, Imvax, Merck (DSMB) Medivir, QED, Tyra, Zymeworks (uncompensated); Research grant / Funding (institution): Bristol Myers Squibb, Boehringer Ingelheim, CytomX, Debiopharm, Eli Lilly, Genoscience, Incyte, Loxo @ Lilly, Novartis, Polaris, Pfizer, Zymeworks, Yiviva. C. Morizane: Honoraria (self): Novartis, Yakult Honsha, Teijin Pharma, Taiho Pharmaceutical, Eisai, MSD K.K., AstraZeneca; Advisory / Consultancy: Boehringer Ingelheim, Merck, Taiho Pharmaceutical, AstraZeneca, SERVIER, MSD K.K., Yakult Honsha; Research grant / Funding (institution): Boehringer Ingelheim, Eisai, Yakult Honsha, ONO PHARMACEUTICAL, Taiho Pharmaceutical, J-Pharma, AstraZeneca, Merck biopharma, Daiichi Sankyo RD Novare, Hitachi. K. Ohkawa: Speaker Bureau / Expert testimony: Eisai, Chugai, Century Medical, Takeda Pharmaceutical, Incyte, Hiamitsu Pharmaceutical, Astellas Pharma, Gilead Sciences, Daiichi Sankyo; Research grant / Funding (institution): Towa, Sumitomo Chemical. M. Ueno: Honoraria (self): Boehringer Ingelheim; Research grant / Funding (institution): Boehringer Ingelheim. A. Vogel: Honoraria (self): AstraZeneca, Amgen, BeiGene, Böhringer Mannheim, BMS, BTG, Daichi-Sankyo, EISAI, GSK, Imaging Equipment Ltd (AAA), Incyte, Ipsen, Jiangsu Hengrui Medicines MSD, PierreFabre, Roche, Servier, Sirtex, Tahio, Terumo; Advisory / Consultancy: AstraZeneca, Amgen, BeiGene, Böhringer Mannheim, BMS, BTG, Daichi-Sankyo, EISAI, Incyte, Ipsen, MSD, PierreFabre, Roche, Servier, Sirtex, Tahio, Terumo. A. Lamarca: Honoraria (self): Travel and educational support from Ipsen, Pfizer, Bayer, AAA, SirtEx, Novartis, Mylan, Delcath Advanza Pharma and Roche. Speaker honoraria from Merck, Pfizer, Ipsen, Incyte, AAA, QED, Servier, Astra Zeneca, EISAI, Roche and Advanz Pharma. Advisory and consultancy honoraria from EISAI, Nutricia Ipsen, QED, Roche, Servier, Boston Scientific, Albireo Pharma, AstraZeneca, Boehringer Ingelheim, GENFIT, TransThera Biosciences and Taiho. Principal Investigator associated Institutional Funding form QED, Merck, Boehringer Ingelheim, Servier, Astra Zeneca, GenFit, Albireo Pharma. Member of the Knowledge Network and NETConnect Initiatives funded by Ipsen. N. Yamamoto: Advisory / Consultancy: Eisai, Takeda, Otsuka, Boehringer Ingelheim, Cmic, Chugai, MERCK, Healios; Speaker Bureau / Expert testimony: ONO, Chugai, Daiichi-Sankyo, Eisai; Research grant / Funding (institution): Astellas, Chugai, Eisai, Taiho, BMS, Pfizer, Novartis, Eli Lilly, AbbVie, Daiichi-Sankyo, Bayer, Boehringer Ingelheim, Kyowa Kirin, Takeda, ONO, Janssen Pharma, MSD, MERCK, GSK, Sumitomo Pharma, Chiome Bioscience, Otsuka, Carna Biosciences, Genmab, Shionogi, TORAY, KAKEN, AstraZeneca, Cmic. M. Javle: Honoraria (self): QED Therapeutics, Inc., AstraZeneca/MedImmune, EMD Serono/Merck, TransThera Biosciences, Incyte, Merck; Advisory / Consultancy: QED Therapeutics, Inc., Oncosil, Incyte, Mundipharma EDO GmbH, AstraZeneca, Merck, EMD Serono, Basilea Pharmaceutical. J. Hu: Honoraria (self): Boehringer Ingelheim (China) Investment Co., Ltd; Full / Part-time employment: Boehringer Ingelheim (China) Investment Co., Ltd. M. Teufel: Full / Part-time employment: Boehringer Ingelheim, Boehringer Ingelheim, Boehringer Ingelheim. A. Märten: Full / Part-time employment: Boehringer Ingelheim. L. Goyal: Advisory / Consultancy: Alentis Therapeutics AG, Black Diamond, H3Biomedicine, Incyte Corp., QED Therapeutics, Servier, Sirtex Medical Ltd., Taiho Oncology; Research grant / Funding (self): AstraZeneca (DMSC); Research grant / Funding (institution): Adaptimmune, Bayer, Eisai, Merck, Macrogenics, Genentech, Novartis, Incyte, Eli Lilly, Loxo Oncology, Relay Therapeutics, QED Therapeutics Inc, Servier, Taiho Oncology, Bristol Meyers Squibb, Nucana, Alentis, Exelixis; Full / Part-time employment: Massachusetts General Brigham, Mass General Hospital Cancer Center. C. Yoo: Honoraria (self): Servier, Bayer, AstraZeneca, Merck Sharp & Dohme, Eisai, Celgene, Bristol Myers Squibb, Debiopharm, Ipsen, Novartis, Boryung Pharmaceuticals, Merck Serono, Mundipharma, Roche; Research grant / Funding (self): Servier, Bayer, AstraZeneca, Ono Pharmaceuticals, Celgene, Ipsen, Boryung Pharmaceuticals, Ildong Pharmaceuticals, CKD Pharmaceuticals, HK inno.N.