REGN5678 Plus Cemiplimab Shows Early, Dose-Dependent Efficacy in mCRPC

Dose-dependent anti-tumor activity was demonstrated with REGN5678 and cemiplimab (Libtayo) in patients with metastatic castration-resistant prostate cancer (mCRPC) in a phase 1/2 study (NCT03972657), according to preliminary results announced in a press release by Regeneron Pharmaceuticals, Inc.¹

"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, a trial investigator and associate professor of Medical Oncology at Columbia University Vagelos College of Physicians and Surgeons, 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."

To carry out the dose-escalation assessment, patients in cohorts 1-5 were treated with a low-dose REGN5678 and cohorts 6-8 received higher doses.

Evidence of dose-dependent antitumor activity was seen within 6 weeks among patients treated with higher doses of REGN5678 plus cemiplimab. In cohort 6, 1 out 4 patients achieved a 100% decrease in PSA and a complete response (CR) in target lesions per RECIST v1.1. Although the patient discontinued treatment due to a grade 3 adverse event (AE), the patient’s condition was resolved with treatment. Further, the 100% decrease in PSA and CR in target lesions has been maintained for approximately 10 months to date, according to the investigators’ assessment.

In cohort 7, 3 out of 8 patients had decreases in PSA of > 99%, 44%, and 22% resulting from REGN5678 and cemiplimab. Grade 3 AEs (aseptic encephalitis and seizure) occurred in 2 of the patients. Both cases have been resolved.

Three out of 4 patients who were treated in cohort 8 showed PSA reductions in PSA of > 99%, > 99%, and 82%. Of those with > 99% PSA decreases, 1 experienced grade 3 mucositis, which has since been resolved. The other patient experienced grade 3 acute inflammatory demyelinating polyradiculopathy, which is ongoing.

Patients treated in cohorts 1-4 showed almost no sign of antitumor activity. One patient out of 17 demonstrated a 22% decrease in PSA. The lack of benefit shown in the low-dose cohorts was consistent with the approximate 6% response rate reported in other trials in which anti-PD1 monotherapy was administered.

Overall, no grade ≥ 3 immune-related adverse events (irAEs) were observed in patients without antitumor activity, and the occurrence of irAEs appeared to be associated with antitumor activity. The safety result was consistent with previous studies in which irAEs were observed with higher doses of anti-PD1 monotherapy. No cases of grade 4 irAEs or grade ≥ 2 cytokine release syndrome have been observed in the trial. One death occurred, which was unrelated to treatment. As the trial continues, investigators are following standard management practice for checkpoint inhibitors to treat patients who experience irAEs.

The first-in-human, open-label study follows a dose-escalation and dose-expansion design. The goal of the study is to evaluate the safety, efficacy, and pharmacokinetics of REGN5678 monotherapy and REGN5678 in combination with cemiplimab 350 mg. In the dose-escalation portion of the study, there is a 3-week safety lead-on of REGN5678 monotherapy prior to the addition of cemiplimab. All treatment in the study is continued until disease progression intolerable adverse events (AEs), withdrawal or consent, or until the study criterion are met.

Safety- and tolerability-related primary end points being assessed in study the include the incidence and severity of treatment-emergent AEs, AEs of special interest, and serious AEs, as well as the number of grade 3 laboratory abnormalities, and the incidence of dose-limiting toxicities. Other primary end points explored in the study are concentration of REGN5678 in serum over time, concentration of REGN5678 in combination with cemiplimab in serum over time, and objective response rate per modified Prostate Cancer Working Group 3 (PCWG3) criteria.²

The study is also evaluating the percentage of patients with ≥ 90% decline of PSA, percentage of patients who have achieved conversion of circulating tumor cell count from baseline of ≥ 5 cells/7.5mL to < 5 cells/7.5mL, the presence or absence of antibodies against REGN5678, and the presence or absence of antibodies against cemiplimab as secondary end points.

To be include in the study, patients must have histologically or cytologically confirmed prostate cancer without pure small cell carcinoma and mCRPC with PSA value at screening that measures ≥ 4 ng/mL and has progressed within 6 months prior to screening. All patients must be previsouly treated with ≥ 2 lines of systemic therapy approved in the metastatic and/or castration-resistant setting along with androgen deprivation therapy.

"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, in the press release.¹ "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.”

_REFERENCES:

_{1. A 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 Pharmaceuticals, Inc. August 3, 2022. Accessed August 3, 2022. https://bit.ly/3SrujyS}

_{2. Study of REGN5678 (Anti-PSMAxCD28) with cemiplimab (Anti-PD-1) in patients with metastatic castration-resistant prostate cancer. ClinicalTrials.gov. Updated March 9, 2022. Accessed August 3, 2022.}