nezastomig (REGN5678) / Regeneron - LARVOL DELTA

Preliminary results from a phase 1/2 study of co-stimulatory bispecific PSMAxCD28 antibody REGN5678 in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC). (ASCO-GU 2023) - P1/2 | "Preliminary data on REGN5678 plus cemiplimab in pts with mCRPC provide first evidence of clinical activity of a CD28 co-stimulatory bispecific antibody in solid tumors. Clinical activity was observed at DLs 30–300 mg. ≥G3 imAEs occurred in pts with PSA declines, suggesting a possible association."

Clinical • Metastases • P1/2 data • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor

A Pilot Presurgical Trial of REGN5678 (Anti-PSMA x CD28) in Patients With High-risk, Localized Prostate Cancer Followed by Radical Prostatectomy (clinicaltrials.gov) - P1/2 | N=42 | Recruiting | Sponsor: M.D. Anderson Cancer Center | Trial completion date: Jun 2026 ➔ Jun 2028 | Trial primary completion date: Jun 2026 ➔ Jun 2028

Trial completion date • Trial primary completion date • Genito-urinary Cancer • Oncology • Prostate Adenocarcinoma • Prostate Cancer • Solid Tumor

A Trial to Find Out if REGN4336 is Safe and How Well it Works Alone and in Combination With REGN5678 for Adult Participants With Advanced Prostate Cancer (clinicaltrials.gov) - P1/2 | N=228 | Recruiting | Sponsor: Regeneron Pharmaceuticals | N=370 ➔ 228 | Trial completion date: Jan 2027 ➔ Mar 2030 | Trial primary completion date: Jan 2027 ➔ Mar 2030

Enrollment change • Trial completion date • Trial primary completion date • Castration-Resistant Prostate Cancer • Genito-urinary Cancer • Oncology • Prostate Adenocarcinoma • Prostate Cancer • Solid Tumor

Updated safety and efficacy results from a phase 1/2 study of nezastomig, a first-in-class co-stimulatory PSMA×CD28 bispecific antibody (bsAb), plus cemiplimab (anti-PD-1) in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) (AACR 2025) - P1/2 | "Updated results provide further evidence of durable clinical anti-tumor activity in mCRPC at nezastomig DLs 30-300 mg QW combined with cemiplimab 350 mg Q3W. In preliminary analyses, encouraging survival outcomes were observed with the higher nezastomig DLs plus cemiplimab. Anti-tumor responses were tightly associated with high-grade imARs."

Bispecific • Clinical • IO biomarker • Metastases • P1/2 data • Castration-Resistant Prostate Cancer • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor

The bispecific antibody KA-3001, targeting PSMA and CD28, specifically enhances T cell activation within prostate tumors (AACR 2024) - "In comparison to REGN5678, KA-3001 exhibits significantly stronger binding to PSMA-expressing prostate tumor cells, along with relatively lower CD28 activation, minimizing toxicity while maintaining anti-tumor efficacy. The BsAb demonstrates neither aggregation nor degradation. In conclusion, the BsAb KA-3001, developed using our common light chain antibody discovery platform, stands out as a promising pre-clinical candidate drug for the treatment of prostate cancer."

Bispecific • IO biomarker • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor

Nezastomig (anti-PSMA×CD28) with or without cemiplimab (anti–PD-1) in patients with metastatic castration-resistant prostate cancer (mCRPC) or metastatic clear cell renal cell carcinoma (mccRCC): A phase 1/2 study. (ASCO-GU 2026) - P1/2 | "Patients with mccRCC must have received ≥1 prior line of systemic therapy approved in the metastatic setting, including anti–PD-1/anti–PD-ligand 1 therapy and either ipilimumab or a tyrosine kinase inhibitor. The dose expansion primary endpoint is a composite response rate of PSA and radiographic responses per modified Prostate Cancer Working Group 3 criteria (mCRPC cohorts) and objective response rate per the Response Evaluation Criteria in Solid Tumors version 1.1 (mccRCC cohorts). This study is open and currently enrolling patients."

Clinical • First-in-human • Metastases • P1/2 data • Castration-Resistant Prostate Cancer • Clear Cell Renal Cell Carcinoma • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • CD28

Hypervigilance: A phase Ib clinical trial to optimize risk-benefit of nezastomig (PSMAxCD28 costimulatory bispecific antibody) plus cemiplimab (anti-PD-1) in patients with metastatic castration-resistant prostate cancer (mCRPC). (ASCO-GU 2026) - P1, P1/2 | "A total of up to 60 patients will be enrolled on study. The study is currently open and enrolling and to date, n=6 patients have been enrolled in the initial cohort (NCT06826768)."

Benefit-risk assessment • Clinical • First-in-human • Metastases • P1 data • Castration-Resistant Prostate Cancer • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • CD4 • CD8 • FOXP3

All-in-one CAR T cell platform for safe and effective targeting of metastatic castration-resistant prostate cancer (SITC 2025) - P1, P1/2 | "In our first-in-human trials of PSMA-CAR T cells armored with a dominant-negative TGF-β receptor II (dnTGFβRII) (NCT03089203, NCT04227275), and in the ongoing REGN5678 αPSMA×CD28 bispecific study (NCT03972657), good responses were observed but accompanied by grade ≥3 cytokine release syndrome (CRS), hemophagocytic lymphohistiocytosis (HLH), and immune effector cell-associated neurotoxicity syndrome (ICANS)...Engineered CAR T cells demonstrated robust in vitro cytotoxicity against heterogeneous prostate cancer cell lines. Furthermore, our preliminary in vivo results show high potency in tumor killing using the LNCaP (STEAP2+, PSMA+) tumor model.Conclusions This all-in-one platform integrates tumor specificity, dual targeting, localized immune activation, and TME resistance, offering a promising strategy for improving the safety and efficacy of CAR T cell therapy in mCRPC and other solid tumors."

CAR T-Cell Therapy • Metastases • Castration-Resistant Prostate Cancer • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • FOLH1 • STEAP2 • TGFB1

The Path Forward for CD28-Targeted T Cell Engagers in Prostate Cancer (PCF 2025) - P1/2 | "Clinical responses have been observed in patients with metastatic castration-resistant prostate cancer (mCRPC) in combination with cemiplimab (anti-PD-1), with grade ≥3 immune-mediated adverse reactions observed in participants with anti-tumor activity (NCT03972657). In the initial treatment levels, presurgical treatment with nezastomig is feasible in patients with high-risk localized prostate cancer planned for radical prostatectomy. The comprehensive evaluation of the prostate tumor microenvironment may enable future biomarker-driven development of nezastomig alone and in combination. Ethics Approval: This study was approved by the MD Anderson Cancer Center Institutional Review Board; protocol number 2023-0135."

IO biomarker • Castration-Resistant Prostate Cancer • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor

An All-in-One ‘Living Drug’ CAR T Cell Platform for Safe and Effective Targeting of Metastatic Castration-Resistant Prostate Cancer (PCF 2025) - P1, P1/2 | "In first-in-human trials of PSMA-targeted CAR T cells armored with a dominant-negative TGF-β receptor II (dnTGFβRII) (NCT03089203, NCT04227275), and the ongoing REGN5678 αPSMA×CD28 bispecific trial (NCT03972657), encouraging responses were observed but accompanied by grade ≥3 cytokine release syndrome (CRS), hemophagocytic lymphohistiocytosis (HLH), and immune effector cell-associated neurotoxicity syndrome (ICANS)...Funding Acknowledgements This work was supported by the PCF Tactical Award 2023 and PCF YI Award 2024. Conflicts of Interest Disclosure Statement The authors declare no conflicts of interest related to this abstract."

CAR T-Cell Therapy • Metastases • Castration-Resistant Prostate Cancer • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • FOLH1 • STEAP2 • TGFB1

R5678-ONC-1879: A Trial to Find Out if REGN5678 (Nezastomig) is Safe and How Well it Works Alone or in Combination With Cemiplimab for Adult Participants With Metastatic Castration-Resistant Prostate Cancer and Other Tumors (clinicaltrials.gov) - P1/2 | N=345 | Recruiting | Sponsor: Regeneron Pharmaceuticals | Trial completion date: Jul 2026 ➔ Nov 2027 | Trial primary completion date: Aug 2025 ➔ Nov 2027

IO biomarker • Trial completion date • Trial primary completion date • Castration-Resistant Prostate Cancer • Clear Cell Renal Cell Carcinoma • Genito-urinary Cancer • Oncology • Prostate Adenocarcinoma • Prostate Cancer • Renal Cell Carcinoma • Solid Tumor • FOLH1

A Ph Ib Study of REGN5678 Plus Cemiplimab in Patients With mCRPC (clinicaltrials.gov) - P1 | N=60 | Recruiting | Sponsor: M.D. Anderson Cancer Center | Not yet recruiting ➔ Recruiting

Enrollment open • Castration-Resistant Prostate Cancer • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor

A phase 1/2 study of nezastomig (anti-PSMA×CD28) with or without cemiplimab (anti–PD-1) in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) and clear cell renal cell carcinoma (ccRCC). (ASCO-GU 2025) - P1/2 | "Pts with metastatic ccRCC must have received ≥1 prior line of systemic therapy approved in the metastatic setting, including an anti-programmed cell death-(ligand) 1 therapy and either ipilimumab and/or a tyrosine kinase inhibitor. Dose expansion primary objective is to assess efficacy of nezastomig (measured by objective response rate per modified Prostate Cancer Working Group 3 criteria [mCRPC cohorts] and per Response Evaluation Criteria in Solid Tumors version 1.1 [ccRCC cohorts]). The study is open and enrolling; 101 pts (97 with mCRPC; 4 with ccRCC) have been enrolled as of September 12, 2024."

Clinical • Metastases • P1/2 data • Castration-Resistant Prostate Cancer • Clear Cell Renal Cell Carcinoma • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor

A Ph Ib Study of REGN5678 Plus Cemiplimab in Patients With mCRPC (clinicaltrials.gov) - P1 | N=60 | Not yet recruiting | Sponsor: M.D. Anderson Cancer Center

New P1 trial • Castration-Resistant Prostate Cancer • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor

Phase 1/2 study of REGN4336 alone or in combination with cemiplimab or nezastomig in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC). (ASCO-GU 2025) - P1/2 | "Module 1 began with REGN4336 administered SC; in addition, Modules 1–3 may evaluate REGN4336 administered IV (+ sarilumab [anti–IL-6] for CRS prophylaxis) to compare tolerability, PK, and immunogenicity across routes. This is the first study to evaluate combined ×CD3 + ×CD28 bsAb in mCRPC. As of Sept 12, 2024, 35 pts have been enrolled, including 4 in Module 3."

Clinical • Combination therapy • IO biomarker • Metastases • P1/2 data • Castration-Resistant Prostate Cancer • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor

A pilot presurgical trial of REGN5678 (Anti-PSMAxCD28) in patients with high-risk, localized prostate cancer followed by radical prostatectomy (SITC 2024) - P1/2 | "The T cell bispecific antibody REGN5678, which co-targets the prostate specific membrane antigen (PSMA) on tumor cells and the CD28 costimulatory domain on T cells, has demonstrated promising efficacy in metastatic castration-resistant prostate cancer (mCRPC) in combination with cemiplimab (anti-PD-1), with grade ≥3 immune-mediated adverse reactions observed in participants with anti-tumor activity (NCT03972657). Based on safety signals from this study and the ongoing first-in-human Phase 1/2 study of REGN5678 in mCRPC (NCT03972657), an amendment may be introduced to expand total enrollment to 42 patients. Ethics Approval This study was approved by the MD Anderson Cancer Center Institutional Review Board; protocol number 2023-0135."

Clinical • IO biomarker • Tumor mutational burden • Castration-Resistant Prostate Cancer • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • TMB

A pilot presurgical trial of REGN5678 (Anti-PSMAxCD28) in patients with high-risk, localized prostate cancer followed by radical prostatectomy (PCF 2024) - P1/2 | "The T cell bispecific antibody REGN5678, which co-targets the prostate specific membrane antigen (PSMA) on tumor cells and the CD28 costimulatory domain on T cells, has demonstrated promising efficacy in metastatic castration-resistant prostate cancer (mCRPC) in combination with cemiplimab (anti-PD-1), with grade ≥3 immune-mediated adverse reactions observed in participants with anti-tumor activity (NCT03972657). The study is currently open and enrolling. The first 6 patients have been treated at an initial starting dose of REGN5678 and completed surgery. No adverse events >Grade 1 have been observed."

Clinical • IO biomarker • Tumor mutational burden • Castration-Resistant Prostate Cancer • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • TMB

A Pilot Presurgical Trial of REGN5678 (Anti-PSMA x CD28) in Patients With High-risk, Localized Prostate Cancer Followed by Radical Prostatectomy (clinicaltrials.gov) - P1/2 | N=42 | Recruiting | Sponsor: M.D. Anderson Cancer Center | Trial primary completion date: Jun 2024 ➔ Jun 2026

Trial primary completion date • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor

A Trial to Find Out if REGN4336 is Safe and How Well it Works Alone and in Combination With Cemiplimab or REGN5678 for Adult Participants With Advanced Prostate Cancer (clinicaltrials.gov) - P1/2 | N=370 | Recruiting | Sponsor: Regeneron Pharmaceuticals | N=199 ➔ 370 | Trial completion date: Aug 2026 ➔ Jan 2027 | Trial primary completion date: Aug 2026 ➔ Jan 2027

Combination therapy • Enrollment change • Metastases • Trial completion date • Trial primary completion date • Genito-urinary Cancer • Metastatic Castration-Resistant Prostate Cancer • Oncology • Prostate Cancer • Solid Tumor

A Pilot Presurgical Trial of REGN5678 (Anti-PSMA x CD28) in Patients With High-risk, Localized Prostate Cancer Followed by Radical Prostatectomy (clinicaltrials.gov) - P1/2 | N=42 | Recruiting | Sponsor: M.D. Anderson Cancer Center | Not yet recruiting ➔ Recruiting

Enrollment open • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor

A Pilot Presurgical Trial of REGN5678 (Anti-PSMA x CD28) in Patients With High-risk, Localized Prostate Cancer Followed by Radical Prostatectomy (clinicaltrials.gov) - P1/2 | N=42 | Not yet recruiting | Sponsor: M.D. Anderson Cancer Center

New P1/2 trial • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor

Study of REGN5678 (Anti-PSMAxCD28) With or Without Cemiplimab (Anti-PD-1) in Patients With Metastatic Castration-resistant Prostate Cancer and Other Tumors (clinicaltrials.gov) - P1/2 | N=297 | Recruiting | Sponsor: Regeneron Pharmaceuticals | N=216 ➔ 297 | Trial completion date: Feb 2025 ➔ Jul 2026 | Trial primary completion date: Feb 2024 ➔ Aug 2025

Enrollment change • IO biomarker • Metastases • Trial completion date • Trial primary completion date • Clear Cell Renal Cell Carcinoma • Genito-urinary Cancer • Oncology • Prostate Cancer • Renal Cell Carcinoma • Solid Tumor • FOLH1

Regeneron Reports Second Quarter 2023 Financial and Operating Results (GlobeNewswire) - P1/2 | N=216 | NCT03972657 | Sponsor: Regeneron Pharmaceuticals | "In the ongoing study of REGN5678, a costimulatory bispecific antibody targeting PSMA and CD28 in advanced prostate cancer, the Company has observed antitumor activity in combination with Libtayo as well as with REGN5678 monotherapy. In the Libtayo combination cohort, there have now been two immune-mediated Grade 5 adverse events (death), including one in July 2023. As a result, the Company has discontinued enrollment of patients receiving the combination of REGN5678 and full-dose Libtayo, and plans to explore REGN5678 combinations with lower doses of Libtayo. The Company also plans to enroll patients in a REGN5678 monotherapy cohort, as well as in combination with other immunotherapy modalities."

Enrollment status • P1/2 data • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor

Regeneron Reports Fourth Quarter and Full Year 2022 Financial and Operating Results (GlobeNewswire) - "Select 2023 Milestones: Initiate Phase 3 study for fianlimab (in combination with Libtayo) in perioperative melanoma (mid-2023). Initiate Phase 2/3 studies for fianlimab (in combination with Libtayo) in first-line advanced NSCLC (first half 2023) and Phase 2 study in perioperative NSCLC (second half 2023). Report additional results from Phase 1/2 study of REGN5678 (PSMA and CD28 bispecific antibody) in combination with Libtayo in prostate cancer (2023). Report initial data across solid organ oncology, including for CD3 bispecifics and CD28 costimulatory bispecifics (2023). EC decision on regulatory submission for Libtayo (in combination with chemotherapy) in advanced NSCLC (first half 2023)."

European regulatory • New P2 trial • New P2/3 trial • New P3 trial • P1/2 data • Genito-urinary Cancer • Lung Cancer • Melanoma • Non Small Cell Lung Cancer • Oncology • Prostate Cancer • Skin Cancer • Solid Tumor

Study of REGN5678 (Anti-PSMAxCD28) With Cemiplimab (Anti-PD-1) in Patients With Metastatic Castration-resistant Prostate Cancer (clinicaltrials.gov) - P1/2 | N=216 | Recruiting | Sponsor: Regeneron Pharmaceuticals | N=129 ➔ 216 | Trial completion date: Jul 2024 ➔ Feb 2025 | Trial primary completion date: Jun 2023 ➔ Feb 2024

Enrollment change • Metastases • Trial completion date • Trial primary completion date • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor