A Phase 1/2 Study of REGN5668 (MUC16xCD28, a Costimulatory Bispecific Antibody) Administered in Combination With Other Agents in MUC16 + Malignancies

Overview

Fianlimab (REGN3767) is an investigational, fully human monoclonal antibody targeting LAG-3 being developed primarily in combination with the PD‑1 inhibitor cemiplimab for melanoma and other solid tumors. Multiple phase 3 trials are ongoing in advanced and adjuvant melanoma and in first-line non–small cell lung cancer (NSCLC); no phase 3 efficacy results have been reported as of October 7, 2025. (ascopubs.org)

Mechanism of action

• Target: Lymphocyte activation gene-3 (LAG‑3), an immune checkpoint receptor expressed on activated T cells. Fianlimab binds LAG‑3 to relieve inhibitory signaling; when combined with PD‑1 blockade (cemiplimab), dual checkpoint inhibition aims to enhance antitumor T‑cell activity. (ascopubs.org)

Efficacy

Advanced melanoma (phase 1, multicohort; fianlimab 1600 mg Q3W + cemiplimab 350 mg Q3W) - PD‑1–naïve advanced disease: ORR 63% in two independent cohorts (n=40 each); combined across three cohorts without prior anti‑PD‑1 for advanced disease (n=98), ORR 61.2% with median PFS 13.3 months (95% CI, 7.5–NE). CR rates were 12–15% across PD‑1–naïve cohorts. (ascopubs.org) - Prior anti‑PD‑1 in the adjuvant setting (relapse after adjuvant therapy; n=13 within a cohort of n=18): ORR 61.5% and median PFS 12 months (95% CI, 1.4–NE). (ascopubs.org) - Prior anti‑PD‑1 for advanced disease (n=15): ORR 13.3% and median PFS 1.5 months (95% CI, 1.3–7.7). (ascopubs.org) - Post hoc/independent review updates: In a combined analysis of PD‑1–naïve cohorts (n=98) with longer follow‑up, ORR 57% by BICR (CR 25%, PR 33%) was reported, with activity observed irrespective of baseline LAG‑3 or PD‑L1 expression. (onclive.com)

Ongoing phase 3 melanoma trials (no results yet) - First‑line unresectable/metastatic melanoma: fianlimab + cemiplimab versus pembrolizumab; primary endpoint PFS; estimated sample size ~1,500+. (ascopubs.org) - Adjuvant high‑risk resected melanoma: fianlimab + cemiplimab versus pembrolizumab (double‑blind, three‑arm design). (ascopubs.org) - Additional phase 3 head‑to‑head versus relatlimab+nivolumab is enrolling. (yalemedicine.org)

NSCLC (ongoing; no results yet) - Two randomized phase 2/3 trials: (1) PD‑L1 ≥50% tumors—fianlimab + cemiplimab versus cemiplimab; (2) all‑comers with chemotherapy—fianlimab + cemiplimab + chemotherapy versus cemiplimab + chemotherapy. (ascopubs.org)

Safety

Across the melanoma phase 1 cohorts of fianlimab + cemiplimab: - Grade ≥3 treatment‑emergent AEs occurred in 44% of patients; grade ≥3 treatment‑related AEs in 22%. An increased incidence of adrenal insufficiency was noted (any‑grade 12%, grade 3–4 4%) relative to typical PD‑1 monotherapy experience; otherwise, the safety profile was broadly comparable to PD‑1 inhibitors. Common AEs included fatigue and rash. (ascopubs.org)

Further reading

• Phase I study in advanced melanoma (peer‑reviewed, full text): Journal of Clinical Oncology. (ascopubs.org)
• ASCO 2021 meeting abstract reporting early melanoma activity and safety. (ascopubs.org)
• First‑in‑human dose‑escalation study (mechanism, dose selection): Clinical Cancer Research. (aacrjournals.org)
• Phase 3 trial synopsis: first‑line unresectable/metastatic melanoma (NCT05352672). (ascopubs.org)
• Phase 3 trial synopsis: adjuvant high‑risk resected melanoma (NCT05608291). (ascopubs.org)
• Phase 2/3 NSCLC trial synopses (NCT05785767; NCT05800015). (ascopubs.org)

Notes: Efficacy figures above derive from early‑phase studies; confirmatory phase 3 outcomes are pending as of October 7, 2025. (ascopubs.org)

Last updated: Oct 2025

Overview

REGN5668 is an investigational MUC16×CD28 costimulatory bispecific antibody being developed for MUC16-positive malignancies (primarily recurrent ovarian, fallopian tube, and primary peritoneal cancers; some study modules also include endometrial cancer). It is in a first‑in‑human, multi‑module Phase 1/2 program (NCT04590326), with combinations that include the PD‑1 inhibitor cemiplimab and/or the MUC16×CD3 T‑cell engager ubamatamab (REGN4018). As of October 7, 2025, human efficacy data are limited to early Phase 1 dose‑escalation results presented at ESMO Immuno‑Oncology 2023. (ascopubs.org)

Mechanism of action

REGN5668 binds the tumor antigen MUC16 on cancer cells and the costimulatory receptor CD28 on T cells, providing localized “signal 2” costimulation intended to enhance T‑cell activity against MUC16‑expressing tumors. The approach is designed to synergize with PD‑1 blockade and/or a CD3 bispecific (ubamatamab) that provides “signal 1.” (mycancergenome.org)

Clinical development

• Trial design: Phase 1/2, open‑label, multi‑center study with dose escalation and expansion. Modules evaluate REGN5668 with cemiplimab, with cemiplimab plus fianlimab, or with ubamatamab (with or without sarilumab). Key objectives include safety, pharmacokinetics, and preliminary antitumor activity by RECIST 1.1 and iRECIST. Estimated primary completion March 2027. (cdek.pharmacy.purdue.edu)

Efficacy

• ESMO IO 2023 Phase 1 dose‑escalation (poster 127P; data cutoff July 14, 2023): Among 28 heavily pretreated platinum‑experienced ovarian cancer patients who received weekly REGN5668 (0.3–300 mg) with cemiplimab added on day 21–28, there was 1 confirmed partial response (59% target lesion reduction) at the 300‑mg dose and 6 patients (21%) with stable disease. One CA‑125 response was reported in the same patient with a partial response. Dose escalation was ongoing with plans to open a 1000‑mg cohort. (oncologypro.esmo.org)

Note: No randomized data or mature response rates beyond these initial findings have been reported publicly to date. (oncologypro.esmo.org)

Safety

• In the ESMO IO 2023 dose‑escalation cohort (n=28), the most common treatment‑related adverse events were fatigue (32%), nausea (29%), and pain (18%). Infusion‑related reactions and cytokine release syndrome occurred in 14% of patients, all grade 1–2. One patient experienced a grade ≥3 treatment‑related adverse event (fatigue). No dose‑limiting toxicities were observed, and no treatment‑related deaths or discontinuations were reported in this analysis. (oncologypro.esmo.org)

Further reading

• ESMO IO 2023 abstract/poster (127P): REGN5668 (MUC16×CD28) with cemiplimab in recurrent ovarian cancer – Phase 1 dose‑escalation results. (oncologypro.esmo.org)
• Trial in progress (ASCO 2021 TPS abstract): Phase I/II study of REGN5668 with cemiplimab or with REGN4018 in recurrent ovarian cancer. (ascopubs.org)
• Gynecologic Oncology meeting abstract (trial design overview). (gynecologiconcology-online.net)
• Study listings and details: Dana‑Farber, UChicago/ClinicalTrials.gov‑linked pages, and registry summaries (NCT04590326). (dana-farber.org)
• Background on mechanism and target from curated drug knowledgebase (NCI Thesaurus entry via My Cancer Genome). (mycancergenome.org)

If newer peer‑reviewed clinical results are published, they were not identified in searches up to October 7, 2025. (oncologypro.esmo.org)

Last updated: Oct 2025

Overview

Ubamatamab (REGN4018) is an investigational, IgG-like bispecific T‑cell–engaging antibody being developed by Regeneron for MUC16‑expressing solid tumors, particularly recurrent ovarian cancer; phase 1/2 development is ongoing with randomized phase 2 expansion cohorts opened in 2024 and additional cohorts in MUC16+ endometrial cancer. (pubmed.ncbi.nlm.nih.gov)

Mechanism of action

• Target: Bridges MUC16 on tumor cells to CD3 on T cells, triggering local T‑cell activation and cytotoxicity. Binding and activity were minimally affected by soluble CA‑125 (shed MUC16) in preclinical testing. (pubmed.ncbi.nlm.nih.gov)
• Preclinical data: Demonstrated MUC16‑directed T‑cell activation and antitumor activity in xenograft and humanized murine models; was well tolerated in cynomolgus monkeys. Anti–PD‑1 co‑treatment enhanced activity in vivo, informing clinical combination with cemiplimab. (pubmed.ncbi.nlm.nih.gov)

Clinical development

• Ongoing phase 1/2 trial (NCT03564340) evaluates ubamatamab alone and with cemiplimab in recurrent ovarian cancer and in MUC16+ endometrial cancer. The phase 2 part includes randomized cohorts testing ubamatamab 250 mg or 800 mg IV every 3 weeks (Q3W) with step‑up priming, and a combination arm with cemiplimab 350 mg Q3W. (oncologypro.esmo.org)

Efficacy

Early, nonrandomized phase 1 dose‑escalation results (conference presentations) in heavily pretreated recurrent ovarian cancer:

• Monotherapy (ESMO 2022/ESMO Gynaecological Cancers 2023, n=78 treated; efficacy set n=42 who received ≥1 full dose ≥20 mg):
• Objective response rate (ORR): 14.3% (95% CI 5.4–28.5).
• Disease control rate (DCR): 57.1% (41.0–72.3).
• Median duration of response (DoR): 12.2 months.

• Exploratory subsets: ORR 20.7% without baseline visceral metastases (n=29) and 30.8% in high MUC16 expression (n=13). (oncologypro.esmo.org)

• Combination with cemiplimab (ESMO 2023 dose‑escalation; 22 patients who received ≥1 dose of cemiplimab):

• ORR: 18.2% (95% CI 5.2–40.3).
• Median DoR: 8.3 months (95% CI 4.2–not estimable).
• CA‑125 response: 22.7% (95% CI 7.8–45.4).
• 6‑ and 12‑mo PFS rates: 47.6% and 23.8%, respectively. (oncologypro.esmo.org)

Note: As of October 2025, randomized phase 2 results have not yet been reported publicly; the trial remains ongoing. (fdaaa.trialstracker.net)

Safety

• Monotherapy (phase 1 dose escalation): Most common treatment‑emergent adverse events (TEAEs) were pain (87%) and cytokine release syndrome (CRS; 73%, all grade 1–2), mainly during weeks 1–2 of step‑up dosing. Common grade ≥3 TEAEs included anemia (~23–24%) and abdominal pain (~19–21%). No clear dose–response relationship in safety from 20–800 mg. (oncologypro.esmo.org)
• Combination with cemiplimab: Similar TEAE profile with pain (83%) and CRS (69%, all grade 1–2) most frequent; grade ≥3 events included anemia (26%), pain (20%), and neutropenia (11%). A grade 4 haemophagocytic lymphohistiocytosis (HLH) case occurred at a higher ubamatamab dose (450 mg) during escalation. Ubamatamab PK was not impacted by cemiplimab. (oncologypro.esmo.org)

Step‑up dosing is used to mitigate CRS risk in both monotherapy and combination regimens, and phase 2 employs Q3W maintenance dosing after the priming phase. (oncologypro.esmo.org)

Trial access and status

• Master phase 1/2 trial: NCT03564340; actively enrolling expansion cohorts (multiple U.S. sites). (dana-farber.org)
• Additional disease‑specific exploration includes a phase 2 study in MUC16‑expressing SMARCB1‑deficient malignancies (NCT06444880; initiated Oct 2024). (fdaaa.trialstracker.net)

Further reading

• Crawford A, et al. A Mucin 16 bispecific T cell–engaging antibody for the treatment of ovarian cancer. Sci Transl Med. 2019. (Preclinical characterization) (pubmed.ncbi.nlm.nih.gov)
• ESMO 2022 mini‑oral: Ubamatamab monotherapy dose‑escalation results in recurrent ovarian cancer. (Meeting resource summary) (oncologypro.esmo.org)
• ESMO 2023: Ubamatamab plus cemiplimab dose‑escalation results. (Meeting resource summary) (oncologypro.esmo.org)
• ASCO 2024 JCO abstract: Phase 1/2 study design and randomized phase 2 overview. (oncologypro.esmo.org)
• Regeneron press summary of ESMO data (for context alongside scientific sources). (investor.regeneron.com)

ClinicalTrials.gov and major cancer center listings can be consulted for site availability and eligibility details for ongoing cohorts (NCT03564340). (dana-farber.org)

Last updated: Oct 2025

Key Inclusion Criteria:

1. Ovarian Cancer Cohorts Only: Has histologically or cytologically confirmed diagnosis of advanced epithelial ovarian cancer (except carcinosarcoma), primary peritoneal, or fallopian tube cancer that has received at least 1 line of platinum-based systemic therapy as defined in the protocol

2. Expansion cohorts only: Has at least 1 lesion that is measurable by RECIST 1.1 as described in the protocol.

3. Has a serum CA-125 level ≥2x ULN (in screening, not applicable to endometrial cohorts)

4. Has adequate organ and bone marrow function as defined in the protocol

5. Has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.

6. Has a life expectancy of at least 3 months

7. Endometrial Cancer Cohorts Only: histologically confirmed endometrial cancer that has progressed or recurrent after prior anti-PD-1 therapy and platinum-based chemotherapy as described in the protocol

Key Exclusion Criteria:

1. Current or recent (as defined in the protocol) treatment with an investigational agent, systemic biologic therapy, or anti-cancer immunotherapy

2. Has had another malignancy within the last 5 years that is progressing, requires active treatment, or has a high likelihood of recurrence as defined in the protocol

3. Prior treatment with a Mucin 16 (MUC16)-targeted therapy

4. Ovarian Expansion cohorts only: More than 5 prior lines of systemic therapy

5. Has any condition that requires ongoing/continuous corticosteroid therapy as defined in the protocol within 1 week prior to the first dose of study drug

6. Has ongoing or recent (within 5 years) evidence of significant autoimmune disease that required treatment with systemic immunosuppressive treatments as defined in the protocol

7. Has untreated or active primary brain tumor, CNS metastases, leptomeningeal disease, or spinal cord compression as defined in the protocol

8. Has history of clinically significant cardiovascular disease as defined in the protocol

9. Has known allergy or hypersensitivity to cemiplimab and/or components of study drug(s).

Note: Other protocol-defined Inclusion/Exclusion criteria apply