nezastomig (REGN5678) / Regeneron - LARVOL DELTA

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."

Clinical • IO biomarker • Metastases • P1/2 data • 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

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."

IO biomarker • 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

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

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

REGN5678 Plus Cemiplimab Shows Early, Dose-Dependent Efficacy in mCRPC (Targeted Oncology) - P1/2 | N= NA | (NCT03972657) | "'In past clinical trials, metastatic castration-resistant prostate cancer has been largely unresponsive to PD-1 inhibition and immunotherapy in general, leaving patients with inadequate treatment options, a poor prognosis and an expected survival of one to two years depending on the treatment history,' said Mark Stein, MD...in a press release. 'These initial data provide the first clinical evidence indicating that a costimulatory bispecific antibody may synergistically combine with an anti-PD-1 agent such as Libtayo to enable activity against a tumor class previously resistant to anti-PD-1 immunotherapy. We look forward to further investigating the safety and efficacy of this combination.'"

Media quote • P2 data

Novel Costimulatory Bispecific Antibody Shows Encouraging Anti-tumor Activity When Combined with PD-1 Inhibitor Libtayo (cemiplimab) in Advanced Metastatic Castration-resistant Prostate Cancer (mCRPC) (PRNewswire) - P1/2 | N=129 | NCT03972657 | Sponsor: Regeneron Pharmaceuticals | "At the lowest dose levels (cohorts 1-5), there was almost no evidence of anti-tumor activity, with only 1 of 17 patients showing a decrease (22%) in PSA...Cohort 6: 1 of 4 patients experienced a 100% decrease in PSA and a complete response (CR) in target lesions based on RECIST 1.1 criteria. The patient discontinued therapy due to a Gr3 irAE of the skin (that was considered to be a recurrence of a pre-existing condition, and has resolved with treatment per investigator report)...Cohort 7: 3 of 8 patients experienced decreases in PSA of >99%, 44% and 22%. Two of these three patients had a Gr3 AE (aseptic encephalitis and seizure, respectively, both of which have resolved)...Cohort 8: 3 of 4 patients experienced decreases in PSA of >99%, >99% and 82%. Of the two patients with >99% PSA reductions, one experienced a Gr3 case of mucositis (resolved)..."

Biomarker • P1/2 data • Genito-urinary Cancer • Oncology • Prostate Cancer

Cemiplimab (PD-1 inhibitor) Induced Rash and Mucositis (AAAAI 2022) - "The patient is a 69-year-old male with metastatic prostate cancer, who was enrolled in a clinical trial with REGN5678 (anti-PSMA x CD28) and PD-1 inhibitor cemiplimab, presenting with pruritic rash and mucositis approximately 4 weeks after the initiation of cemiplimab. Although similar mucocutaneous symptoms have been reported in the literature with other immune-checkpoint inhibitors, this is the first reported case of cemiplimab-induced rash and mucositis. This case illustrates the importance of timely recognition of potential mucocutaneous symptoms associated with immune checkpoint inhibitors such as cemiplimab, in order to avoid delays in diagnosis and initiate appropriate treatment."

Allergy • Dermatitis • Dermatology • Dermatopathology • Genito-urinary Cancer • Immune Modulation • Immunology • Inflammation • Lichen Planus • Mucositis • Oncology • Prostate Cancer • Solid Tumor

Regeneron Reports Fourth Quarter and Full Year 2021 Financial and Operating Results (PRNewswire) - "Select 2022 Milestones...REGN5458 (BCMA and CD3 Bispecific Antibody)- Report results from potentially pivotal Phase 2 study in multiple myeloma, Initiate Phase 1 and Phase 3 studies exploring combinations with standard of care and additional combination studies; Odronextamab (CD20 and CD3 Bispecific Antibody)- Report additional results from potentially pivotal Phase 2 study in B-cell non-Hodgkin lymphoma (B-NHL), Initiate OLYMPIA Phase 3 program and additional combination studies; Solid Tumor Bispecific Antibodies - Report results from REGN4018 (MUC16 and CD3 bispecific antibody) Phase 1 study in platinum-resistant ovarian cancer, Report results from REGN5678 (PSMA and CD28 bispecific antibody) Phase 1 study in prostate cancer, Report results from REGN5093 (bispecific antibody targeting two distinct MET epitopes) Phase 1 study in MET-altered advanced NSCLC."

Clinical data • Trial status • Cervical Cancer • Genito-urinary Cancer • Gynecologic Cancers • Hematological Malignancies • Lung Cancer • Multiple Myeloma • Non Small Cell Lung Cancer • Non-Hodgkin’s Lymphoma • Oncology • Ovarian Cancer • Prostate Cancer • Solid Tumor

[VIRTUAL] A phase I/II study of REGN5678 (Anti-PSMAxCD28, a costimulatory bispecific antibody) with cemiplimab (anti-PD-1) in patients with metastatic castration-resistant prostate cancer. (ASCO 2020) - P1/2 | "REGN5678 is a human IgG4-based, first-in-class costimulatory bsAb designed to target prostate tumors by bridging prostate specific membrane antigen expressing tumor cells with the costimulatory receptor, CD28, on T cells, and providing amplified T-cell receptor-CD3 complex-mediated T-cell activation within the tumor through the activation of CD28 signaling. This study is currently open to enrollment. Research Funding: Regeneron Pharmaceuticals Inc."

Clinical • P1/2 data • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • CD8

[VIRTUAL] A phase I/II study of REGN5678 (Anti-PSMAxCD28, a costimulatory bispecific antibody) with cemiplimab (anti–PD-1) in patients with metastatic castration-resistant prostate cancer. (ASCO-GU 2021) - P1/2 | "REGN5678 is a human IgG4-based, first-in-class costimulatory bsAb designed to target prostate tumors by bridging prostate specific membrane antigen expressing tumor cells with the costimulatory receptor, CD28, on T-cells, and providing amplified T-cell receptor-CD3 complex-mediated T-cell activation within the tumor through the activation of CD28 signaling. At selected sites, prostate-specific membrane antigen PET/CT scans are performed at baseline and select time points on study. This study is currently open to enrollment."

Clinical • P1/2 data • Genito-urinary Cancer • Oncology • Prostate 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=129; Recruiting; Sponsor: Regeneron Pharmaceuticals; Trial primary completion date: Jun 2024 ➔ Jun 2023

Clinical • Trial primary completion date • Genito-urinary Cancer • Oncology • Prostate 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=129; Recruiting; Sponsor: Regeneron Pharmaceuticals; Trial completion date: Sep 2025 ➔ Jun 2024; Trial primary completion date: Sep 2025 ➔ Jun 2024

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

[VIRTUAL] Combinatorial Approaches to Enhance Bispecific Anti-Tumor Efficacy (PEGS 2020) - "This presentation will describe Regeneron’s bispecific platform and present preclinical data on REGN4018, a clinical-stage, T cell-engaging, bispecific-targeting Muc16 for solid tumor indications. In addition, status updates on Regeneron’s other clinical-stage bispecific antibodies (REGN1979, REGN5458, REGN5678) will be presented, as well as a discussion of new combinatorial approaches being taken to enhance bispecific anti-tumor efficacy."

Clinical • Oncology • Solid Tumor • CA125 • MUC16