REGN5678 Plus Cemiplimab Demonstrates Early Activity in mCRPC

Pipeline Report: August 2022

The novel PSMAxCD38 costimulatory bispecific antibody REGN5678 has shown encouraging efficacy in combination with cemiplimab in patients with advanced metastatic castration-resistant prostate cancer, according to preliminary findings from an ongoing phase 1/2 trial (NCT03972657).

Mark Stein, MD

Mark Stein, MD

The novel PSMAxCD38 costimulatory bispecific antibody REGN5678 has shown encouraging efficacy in combination with cemiplimab-rwlc (Libtayo) in patients with advanced metastatic castration-resistant prostate cancer (mCRPC), according to preliminary findings from an ongoing phase 1/2 trial (NCT03972657).

The results showed that the higher dose levels evaluated in cohorts 6 through 8 were associated with improved anti-tumor activity within 6 weeks of starting the combination treatment. Safety data showed no evidence of grade 3 or greater immune-related adverse effects (irAEs) in nonresponding patients. Previous findings demonstrated an association between the occurrence of irAEs and anti-tumor activity.

In cohort 6 (n = 4), 1 patient experienced a 100% reduction in PSA and a complete response (CR) in target lesions based on RECIST v1.1 criteria, which was maintained for approximately 10 months. Ultimately, the patient discontinued therapy because of a grade 3 irAE of the skin that has resolved with treatment.

In cohort 7 (n = 8), 3 patients experienced a reduction in PSA of more 99%, 44%, and 22%, respectively. Two of these patients had a grade 3 AE of aseptic encephalitis and seizure, respectively, both of which have resolved.

In cohort 8 (n = 4), 3 patients experienced reductions in PSA of more than 99% (n = 2) and 82%. Of the 2 patients with greater than 99% PSA reductions, 1 experienced grade 3 mucositis that resolved and the other experienced grade 3 acute inflammatory demyelinating polyradiculopathy.

“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,” Mark Stein, MD, a trial investigator and associate professor of medical oncology at Columbia University Vagelos College of Physicians and Surgeons, said 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.”

In this first-in-human, open-label phase 1/2 trial, investigators are evaluating the agent for safety and efficacy in patients with advanced mCRPC who have experienced disease progression on multiple anti-androgen therapies. In the phase 1 dose-escalation portion, patients are started on weekly doses of the REGN5678 monotherapy for 3 weeks, which is then continued in combination with standard dose cemiplimab.

The primary end points are safety, tolerability, and pharmacokinetics. The key secondary end point is objective response rate defined as at least a 50% reduction of prostate-specific antigen (PSA) from baseline and/or tumor shrinkage.

Preliminary data from the ongoing dose-escalation portion of the trial captures 33 patients across 8 dose level cohorts. At the lowest dose levels evaluated in cohorts 1 through 5, investigators observed minimal anti-tumor activity, with only 1 of 17 patients showing a reduction in PSA of 22%.

Stein and colleagues have observed no grade 4 irAEs or grade 2 or greater cytokine release syndrome in the trial to date. There was 1 death reported but that was deemed to be unrelated to treatment.

“Through extensive preclinical research, we hypothesized that augmenting T-cell costimulation alongside PD-1 inhibition could be a key to turning immunologically ‘cold’ tumors ‘hot,’” said George D. Yancopoulos, MD, PhD, president, and chief scientific officer at Regeneron. “These preliminary data for our PSMAxCD28 costimulatory bispecific provide the first clinical evidence supporting the promise of our broader pipeline of costimulatory bispecifics in diverse solid tumors and hematological malignancies. By combining these costimulatory bispecifics with Libtayo or our CD3 bispecifics, we have the opportunity to create novel therapeutic synergies to address some of the most difficult-to-treat cancers.”

Investigators plan to present additional data at an upcoming medical meeting.


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). News release. Regeneron. August 3, 2022. Accessed August 3, 2022.

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