CG0070/Pembrolizumab Combo Shows Promising Efficacy and Tolerability in NMIBC

Roger Li, MD

The oncolytic vaccine CG0070 plus pembrolizumab (Keytruda) demonstrated encouraging response rates and a tolerable safety profile in patients with non–muscle invasive bladder cancer (NMIBC) unresponsive to Bacillus Calmette-Guérin (BCG), according to preliminary data from the phase 2 CORE1 trial (NCT04387461) presented at the 2022 SITC Annual Meeting.

Among 32 evaluable patients, the combination elicited an overall complete response (CR) rate of 87% (n = 28), including 6-, 9-, and 12-month CR rates of 86% (n = 25/29), 86% (n = 18/21), and 73% (n = 11/15), respectively.

“The combination of CG0070 and pembrolizumab appears promising to date based on preliminary data showing efficacy beyond that observed in past studies for either agent alone, in conjunction with a tolerable safety profile in line with the prior adverse effect [AE] profile reported for each agent as monotherapy,” lead study author, Roger Li, MD, of Moffitt Cancer Center, and colleagues, wrote in a poster of the data.

The single-arm CORE1 study assessed the efficacy of CG0070 plus intravenous (IV) pembrolizumab in patients with BCG-unresponsive NMIBC.

CG0070 is a serotype 5 adenovirus designed to express granulocyte-macrophage colony-stimulating factor (GM-CSF) and replicate in tumor cells with mutated or deficient retinoblastoma (Rb). Intravesical CG0070, which is enhanced in the presence of GM-CSF, is designed to target and destroy cancer cells through tumor-selective infection and replication of the virus, followed by cell killing that induces local immune cell inflammation and trafficking to the infected tumor site. The vaccine then stimulates an antitumor immune response by priming and amplifying systemic antitumor immunity, resulting in the induction of tumor antigen–specific T cells that can eliminate uninfected tumor cells, including distant metastases.

The E2F promoter, which has been inserted into the adenovirus backbone place of the wild-type E1a promoter sequence, controls replication and transgene expression. In cells with an aberrant Rb pathway, the E2F transcription factor can bind to the promoter sequence, drive expression of the essential viral genes, and restrict viral replication to the defective tumor cells in the Rb pathway, selectively killing them with minimal damage to normal tissue cells.

The trial enrolled patients with BCG-unresponsive carcinoma in situ (CIS) with or without concurrent Ta or T1 disease to receive intravesical CG0070 at 1 x 1012 vp plus IV pembrolizumab at 400 mg once every 6 weeks. CG0070 was administered weekly for 6 weeks as induction, followed by weekly maintenance instillations for 3 weeks at months 3, 6, 9, 12, and 18. Patients who have persistent CIS or high-grade Ta disease at 3 months were permitted to re-induction with CG0070 weekly for 6 additional weeks. Pembrolizumab treatment continued for up to 24 months.

Response assessment included cystoscopy with biopsy of areas suspicious for disease, performed every 3 months; urine cytology; CT/MRI; and mandatory bladder mapping biopsies at 12 months. High-grade disease recurrence will be considered a disease recurrence.

The primary end point of this trial was CR at 12 months. Secondary end points included CR at any time, progression-free survival, duration of response, cystectomy-free survival, and safety.

Of the 32 patients with evaluable preliminary CR data, 24 had ongoing CRs at data cutoff. Additionally, 4 patients did not respond. Of these patients, 1 discontinued the study treatment at 3 months, 1 discontinued the study treatment at 6 months, and 2 received re-induction at 3 months after no response, 1 of whom also discontinued the study treatment at 6 months.

At a data cutoff of October 3, 2022, the most frequent grade 1 or 2 treatment-related AEs (TRAES) included bladder spasm (n = 13), fatigue (n = 11), pollakiuria (n = 9), dysuria (n = 6), urinary tract infection (n = 5), hematuria (n = 4), micturition urgency (n = 4), and nocturia (n = 4).

Additionally, the investigators observed grade 1/2 TRAEs of abdominal pain, alanine aminotransferase increase, aspartate aminotransferase increase, diarrhea, headache, and hypothyroidism in 3 patients each, and arthralgia, blood creatinine increase, chills, joint stiffness, myalgia, polyuria, pruritis, and urinary tract pain in 2 patients each.

One patient each experienced grade 3 decreased ejection fraction, immune-mediated hepatitis, and decreased neutrophil count.

Trial enrollment has been completed, and data readout on all patients through a minimum of 12 months is expected in 2023, the study authors concluded.

Reference

1. Li R, Steinberg GD, Lamm D, et al. CORE1: phase 2, single-arm study of CG0070 combined with pembrolizumab in patients with non–muscle invasive bladder cancer (NMIBC) unresponsive to Bacillus Calmette-Guerin (BCG). Presented at: 2022 SITC Annual Meeting; November 8-12, 2022. Boston, MA. Abstract 666.