57O - A phase I/II multicenter, first-in-human study of DB-1311/BNT324 (a novel B7H3 ADC) in patients with advanced solid tumors

Background

DB-1311/BNT324 is an investigational, next-generation topoisomerase-I-inhibitor-based ADC targeting the immune checkpoint protein B7H3 that is overexpressed in many solid tumors and correlates with poor prognosis. Preclinical studies showed potent antitumor activity and a favorable PK profile.

Methods

This phase I/2, multicenter, first-in-human, dose escalation/expansion study is evaluating the safety, PK, and efficacy of DB-1311/BNT324 in patients (pts) with pretreated advanced/metastatic solid tumors unselected for B7H3 expression.

Results

As of May 24, 2024, 126 pts from the US, Australia and China had received ≥1 dose of DB-1311/BNT324 across 5 dose cohorts (between 3–12 mg/kg IV Q3W), with 93 (74%) still on treatment. Median age was 62 years (range 34–84), while most pts were male (92 [73%]), Asian (67 [53%]) and had ECOG PS 1 (94 [75%]). DLTs were reported in 4 pts (2 at 10.5 mg/kg and 2 at 12.0 mg/kg). The MTD was established at 9 mg/kg. Across all doses, treatment-emergent adverse events (TEAEs) occurred in 114 (90.5%) pts, considered treatment related in 102 (81.0%) and were Grade ≥3 (G≥3) in 53 (42.1%) pts (related in 40 pts [31.7%]). Any grade TEAEs occurring in ≥20% of pts across all doses were nausea (46.0% [G≥3: 2.4%]), neutrophil count decreased (34.9% [G≥3: 15.9%]), anemia (32.5% [G≥3: 7.1%]), platelet count decreased (25.4% [G≥3: 6.3%]), and WBC count decreased (23.0% [G≥3: 4.8%]). TEAEs led to dose reduction in 12 (9.5%) pts and discontinuation in 7 (5.6%) pts. The exposure of ADC, total antibody and payload increased in an approximate dose-proportional manner with a half-life ∼3-4 days for the ADC and ∼5 days for the payload. Preliminary efficacy from 77 response-evaluable pts showed 22 partial responses (PR) and 42 stable diseases, for an unconfirmed ORR of 28.6% (95% CI 18.9, 40.0) and a DCR of 83.1% (95% CI 72.9, 90.7). In pts with SCLC (n=33), unconfirmed ORR was 45.5% with higher ORR in pts without prior topotecan (56.0%, n=25) or prior IO (55.6%, n=9). PRs were also observed in 3 pts with CRPC, 3 pts with NSCLC and 1 pt with BTC.

Conclusions

DB-1311/BNT324 had a manageable safety profile with low rates of G≥3 hematological events and promising antitumor activity, particularly in pts with advanced/metastatic SCLC.

Clinical trial identification

NCT05914116 First Posted: June 22, 2023.

Editorial acknowledgement

Legal entity responsible for the study

DualityBio Inc. in collaboration with BioNTech.

Funding

DualityBio Inc. in collaboartion with BioNTech.

Disclosure

L. Wu: Financial Interests, Personal, Advisory Role: AstraZeneca, Roche, Bristol Myers Squibb, MSD, Pfizer, Lilly, Boehringer Ingelheim, Merck, Innovent, Hengrui; Financial Interests, Personal, Full or part-time Employment: Burning Rock Biotech. A. Schmidt: Financial Interests, Personal, Advisory Role: Astellas, Eisai; Financial Interests, Personal, Other, Educational support: Merck, BMS. R. Tibes: Financial Interests, Personal, Full or part-time Employment: BioNTech; Financial Interests, Personal, Stocks or ownership: BioNTech. X. Lu: Financial Interests, Personal, Full or part-time Employment: Duality Biologics; Financial Interests, Personal, Stocks or ownership: Duality Biologics. V. Gu: Financial Interests, Personal, Full or part-time Employment: Duality Biologics; Financial Interests, Personal, Stocks/Shares: Duality Biologics. A.E. Lisberg: Financial Interests, Personal, Other, Consulting: Bayer, IQVIA, Leica Biosystems, Jazz Pharmaceuticals; Financial Interests, Personal, Other, Advisory Board and Consulting: Daiichi Sankyo, Inc., AstraZeneca, Novocure, Eli Lilly, Oncocyte, Novartis, Regeneron, Janssen Oncology, Sanofi group of companies, Molecular Axiom, Amgen, G1 Therapeutics, Bristol Myers Squibb, MorphoSys, Pfizer; Financial Interests, Personal, Other, Consulting, lectures, advising: Platformq; Financial Interests, Personal, Other, Consulting, advising, lectures: HMP Global, MJH Associates, Med Learning, Clinical Care Options, Physicians Educational Resources, Curio Sciences, Vaniam Group, Medscape, Projects in Knowledge, Aptitude Health, MOASC, SITC; Financial Interests, Personal, Invited Speaker: Research to Practice, DAVA, Research to Practice; Financial Interests, Personal, Full or part-time Employment, EmploymentImmediate family member (wife): Boston Scientific; Financial Interests, Personal, Stocks/Shares, Stock (<5% equity)Immediate family member (wife): Boston Scientific; Financial Interests, Institutional, Research Grant, Local PI for multiple trials and Global PI, as well as steering committee chair for U303: Daiichi Sankyo, Inc.; Financial Interests, Institutional, Research Grant, Local PI for multiple trials: Calithera, AstraZeneca; Financial Interests, Institutional, Research Grant, Local PI and externally sponsored research grant: Dracen; Financial Interests, Institutional, Research Grant, Local PI: WindMIL, Effector Therapeutics; Financial Interests, Institutional, Research Grant, Local PI for multiple trials and global PI for multiple trials: Duality Biologics; Financial Interests, Institutional, Research Grant, 2019 Career Development Award: LUNGevity; Financial Interests, Institutional, Research Grant, NIH-NCI K08 CA245249: NIH/NCI; Non-Financial Interests, Personal, Member: ASCO, ESMO, IASLC, AACR. All other authors have declared no conflicts of interest.