1045P - Safety and preliminary clinical activity of JNJ-78306358 (JNJ-358), an HLA-G and CD3 bispecific antibody, for the treatment of advanced stage solid tumor

Background

HLA-G has limited normal tissue expression but is expressed in a variety of human cancers where it may have an immune evasion function. JNJ-6358 is a bispecific antibody that redirects T cells to kill HLA-G-expressing tumor cells.

Methods

This phase 1 dose escalation study evaluated the safety, pharmacokinetics, pharmacodynamics, and preliminary antitumor activity of JNJ-6358 administered subcutaneously to adult participants (pts) with metastatic or unresectable solid tumors with a high prevalence of HLA-G expression: renal cell carcinoma (RCC), ovarian cancer (OC), and colorectal cancer (CRC). Dose escalation followed a modified continual reassessment method.

Results

As of 09 February 2023, 39 pts (23 with CRC, 10 with OC, and 6 with RCC) were dosed once weekly in 7 cohorts. Premedication included high dose corticosteroids. The majority of pts (54%) had 4 or more prior lines of systemic therapy for metastatic disease. The most common treatment-emergent adverse events were cytokine release syndrome (CRS) (49%), ALT/AST increase (39%), injection site erythema (39%), fatigue (36%), and abdominal pain (26%). CRS was G1 or G2 and responded to tocilizumab. Dose limiting toxicities (DLTs) were reported in 4 pts, 2 with G3 increased transaminases, 1 with G3 pneumonitis, and 1 with recurrent G1 CRS requiring dose reduction. G3 DLTs coincided with CRS. No treatment related deaths were reported. There were no objective responses per RECIST. Target lesion reduction >10% from baseline was observed in 5 pts. Two pts had stable disease >40 weeks. HLA-G was detected (IHC H-score > 0) in archival tissue from 12 of 25 pts. No relationship between tumor reduction and baseline HLA-G expression was observed. JNJ-6358 exposure levels increased with dose. Anti-drug antibodies (ADA) were observed in 45% of evaluable pts and were associated with loss of detectable exposure.

Conclusions

JNJ-6358 dose escalation was limited by CRS-associated toxicities, which were only partially mitigated by step-up-dosing and premedication. Considering the CRS-related toxicities and the ADA formation, the Sponsor decided to halt dose escalation. No recommended phase 2 dose was determined.

Clinical trial identification

Clinical Protocol 78306358STM1001, NCT04991740, EudraCT 2021-001646-35 Release date August 5, 2021.

Editorial acknowledgement

Legal entity responsible for the study

Janssen Research & Development, L.L.C.

Funding

Janssen R&D.

Disclosure

R. Geva: Financial Interests, Personal, Other, Honoraria: Roche, MSD, Merck, Medison, Janssen, Pfizer, BMS; Financial Interests, Personal, Advisory Board, 07/2022: AstraZeneca; Financial Interests, Personal, Advisory Board, Ended 3/2022: BOL Pharma; Financial Interests, Personal, Advisory Board: Roche, Ranium, JNJ, Bayer, Oncotest; Financial Interests, Personal, Advisory Board, 06/2022: MSD; Financial Interests, Personal, Other, Travel/Accommodations/Expenses 01/2022: Takeda; Financial Interests, Personal, Other, Travel/Accommodations/Expenses - 06/2022: Medison; Financial Interests, Personal, Other, Options: Pyxis; Financial Interests, Personal, Other, Medical lead: Pyxis. M. Vieito Villar: Non-Financial Interests, Principal Investigator: Roche, BMS, Taiho, Hutchinson Pharma, Novartis, Mundipharma, Enterome, Debiopharm. R. Perets: Financial Interests, Personal, Other, Consultant: Galmed Therapeutics, Gilboa Therapeutics, 1E Therapuetics; Financial Interests, Institutional, Local PI: Jannsen, MSD, BMS, Genentech, Amgen, AbbVie, Ammune; Financial Interests, Institutional, Coordinating PI: Biomica; Non-Financial Interests, Institutional, Product Samples, Antibody for research: AbbVie. E. Calvo: Financial Interests, Personal, Advisory Board: Adcendo, Amunix, Anaveon, AstraZeneca, BMS, Janssen, MonTa, MSD, Nanobiotix, Nouscom, Novartis, Servier, TargImmune, T-knife, Chugai, Elevation Oncology, Ellipses Pharmacy, SyneosHealth, Genmab, Diaccurate; Financial Interests, Personal, Invited Speaker: OncoDNA, PharmaMar, Roche/Genentech; Financial Interests, Personal, Full or part-time Employment, Director, Clinical Research: HM Hospitales Group; Financial Interests, Personal, Full or part-time Employment, Medical Oncologist. Clinical Investigator. Director, Clinical Research: START Madrid - CIOCC (Centro Integral Oncológico Clara Campal); Financial Interests, Personal, Member of Board of Directors, External Independent member of Board of Directors: PharmaMar; Financial Interests, Personal, Ownership Interest: START, Oncoart Associated; Financial Interests, Personal, Steering Committee Member, Member of Data Monitoring Committee: BeiGene, Sanofi, Merus; Financial Interests, Personal, Steering Committee Member: Novartis; Non-Financial Interests, Other, Non-for-profit Foundation. President and co-founder: INTHEOS (Investigational Therapeutics in Oncological Sciences) non-for-profit Foundation; Non-Financial Interests, Advisory Role: PsiOxus; Non-Financial Interests, Other, Chair of the Independent Data Monitoring Committee: EORTC IDMC; Non-Financial Interests, Member of Board of Directors, Non-for-profit Foundation, trustee member: Non-for-profit Foundation PharmaMar; Non-Financial Interests, Advisory Role, Non-for-profit foundation: CRIS Cancer Foundation, non-for-profit ; Non-Financial Interests, Member: ASCO, ESMO, SEOM, EORTC. E. Garralda: Financial Interests, Personal, Advisory Board: Roche, Ellipses Pharma, Boehringer Ingelheim, Janssen Global Services, Seattle Genetics, Alkermes, Thermo Fisher, MabDiscovery, Anaveon, Hengrui, F-Star Therapeutics, Sanofi, Incyte; Financial Interests, Personal, Invited Speaker: MSD, Lilly, Roche, Thermo Fisher, Novartis, Seagen; Financial Interests, Personal, Full or part-time Employment: NEXT Oncology; Financial Interests, Institutional, Funding: Novartis, Roche, Thermo Fisher, AstraZeneca, Taiho; Financial Interests, Institutional, Research Grant: BeiGene, Janssen. R.J. Brown: Financial Interests, Institutional, Full or part-time Employment: Janssen R&D; Financial Interests, Personal, Stocks/Shares: Johnson & Johnson. J. Gregor: Financial Interests, Personal, Full or part-time Employment, Employed by Janssen R&D: Janssen R&D; Financial Interests, Personal, Stocks/Shares, Own shares as part of employment with Janssen R&D: Johnson&Johnson. S. Wu: Financial Interests, Personal, Full or part-time Employment: Janssen Research & Development, Johnson & Johnson; Financial Interests, Personal, Stocks/Shares: Janssen Research & Development, Johnson & Johnson. D. Steinbach: Financial Interests, Personal, Full or part-time Employment: Janssen R&D; Financial Interests, Personal, Stocks/Shares: Institutional Johnson & Johnson. S. Tsun-wen: Financial Interests, Institutional, Full or part-time Employment: Janssen R&D; Financial Interests, Personal, Stocks/Shares: Janssen R&D. Y. Cao: Financial Interests, Institutional, Full or part-time Employment, Johnson & Johnson: Janssen R&D. J. Lauring: Financial Interests, Institutional, Full or part-time Employment: Janssen Research and Development; Financial Interests, Personal, Stocks/Shares: Johnson and Johnson; Financial Interests, Personal, Royalties, I am entitled to receive royalties on genetically engineered cell lines I developed that were licensed to Horizon Discovery under an agreement with Johns Hopkins University.: Horizon Discovery Ltd; Non-Financial Interests, Member: ASCO. V. Moreno Garcia: Financial Interests, Personal, Advisory Board: BMS, Janssen, Roche, Basilea, Bayer, AstraZeneca; Financial Interests, Personal, Full or part-time Employment: START; Financial Interests, Institutional, Local PI, AbbVie, AceaBio, Adaptimmune, ADC Therapeutics, Aduro, Agenus, Amcure, Amgen, Astellas, AstraZeneca Bayer BeiGene BioInvent International AB, BMS, Boehringer, Boheringer, Boston, Celgene, Daiichi Sankyo, DEBIOPHARM ,Eisai, e-Terapeutics, Exelisis, Forma Therapeutics, Genmab, GSK, Harpoon, Hutchison, Immutep, Incyte, Inovio, Iovance, Janssen, Kyowa Kirin, Lilly, Loxo, MedSir, Menarini, Merck, Merus, Millennium, MSD, Nanobiotix, Nektar, Novartis, Odonate Therapeutics, Pfizer, Pharma Mar, PharmaMar, Principia, PsiOxus, Puma, Regeneron, Rigontec, Roche, Sanofi, Sierra Oncology, Synthon, Taiho, Takeda, Tesaro, Transgene, Turning Point Therapeutics, Upshersmith.: Multiple. All other authors have declared no conflicts of interest.