In Advanced Solid Tumors, MK-5890 Shows Promising Safety Results as Monotherapy or in Combination with Pembrolizumab

Ronnie Shapira-Frommer, MD

Ronnie Shapira-Frommer, MD

The anti—CD27 agonist, MK-5890, demonstrated acceptable safety findings when administered as monotherapy and in combination with pembrolizumab (Keytruda) in numerous solid tumors, according to findings of an open-label phase I trial presented by Ronnie Shapira-Frommer, MD, head of the Onco-Gynecological Cancer Unit at The Ella Lemelbaum Institute for Immuno-Oncology, Ramat Gan, Israel, during the Society for Immunotherapy of Cancer’s 34^thAnnual Meeting (SITC 2019).¹

CD27 signaling plays a role in cytotoxic T lymphocyte responses and the survival of activated T cells.²MK-5890 is a monoclonal antibody that binds to CD27 to provide a costimulatory signal that enhances T-cell—mediated responses.

A total of 44 patients were enrolled with 25 patients enrolled in the monotherapy arm and 19 enrolled in the combination arm. Six patients had received treatment with a prior immune checkpoint inhibitor, and the median age was 59.0 (range, 23—77). Seven (15.9%) patients had a primary diagnosis of ovarian cancer, 6 (13.6%) were diagnosed with colorectal and soft tissue sarcoma (13.6%), respectively, 4 (9.1%) patients were diagnosed with breast cancer and 3 (6.8%) were diagnosed with gastrointestinal cancer. There were 2 (4.5%) diagnoses each of cervical, endometrial, head and neck, non–small cell lung cancer, pancreatic and prostate cancer.

The study was composed of 2 phases: a dose escalation and confirmation phase and a dose expansion phase. MK-5890 was tested alone (doses ranging from 2 mg to 700 mg) or with pembrolizumab (fixed dose of 200 mg). Treatment continued until disease progression, unacceptable toxicity, or investigator/patient decision to withdraw. Patients could crossover from the monotherapy arm to the combination arm if disease progression was observed.

In the dose escalation and confirmation phase, the primary objective was safety and tolerability as measured by dose-limiting toxicity and adverse events. Secondary objectives included pharmacokinetic parameters.

In the monotherapy arm, 22 (88%) patients reported treatment-related adverse events (TRAEs) and in the combination arm, 18 (94.7%) patients reported TRAEs. Six (24%) patients receiving MK-5890 monotherapy reported Grade 3/4 adverse events and 4 (21.1%) patients in the combination arm reported Grade 3/4 TRAEs (Table 1).

“There were no treatment-related deaths for either arm,” Shapira-Frommer said, “and 3 patients overall discontinued treatment due to TRAEs.” Dose-limiting toxicities (DLTs) were reported in 4 patients overall, which were attributed to infusion-related reactions.

For the monotherapy arm (n = 25), the most common TRAEs reported in more than 10% of patients were fatigue (28%), infusion-related reaction (28%), nausea (20%), pruritus (16%) and rash (16%). In the combination arm (n = 19), the most common TRAEs were fatigue (36.8%), pruritus (31.6%), nausea (26.3%) and infusion-related reaction (21.1%). Across both treatment arms (N = 44), the most common TRAEs were fatigue (31.8%), infusion-related reaction (25%), nausea (22.7%) and pruritus (22.7%).

Grade 3/4 TRAEs were mild across the treatment arms, as well. In the monotherapy arm, 1 patient each reported having increased aspartate aminotransferase, decreased appetite, hypoxia, infusion-related reaction, increased lipase and pruritus. In the combination arm, 1 patient each was reported to have increased amylase, hypophosphatemia, hypotension and tumor pain.

“Hypotension was reported in 1 patient in the combination arm, probably as a result of an infusion-related reaction,” Shapira-Frommer said.

“Looking at response rates, 1 patient in the monotherapy arm achieved partial response. In the combination arm, 2 patients achieved partial response. In the crossover arm, 5 patients had responses with 2 complete responses and 3 partial responses. Nine patients demonstrated an overall disease control rate, which lasted for more than 6 months: 2 patients in the monotherapy arm, 2 in the combined therapy arm, and 5 in the crossover arm (Table 2).

“We observed early antitumor activity in patients with advanced solid tumors, both in the monotherapy arm and the combination arm and therefore we are enrolling patients in expansion cohorts,” Shapira-Frommer concluded.

N (%)

MK-5890 (n = 25)

MK-5890 + pembrolizumab (n = 19)

Total (N = 44)

Any TRAE

22 (88.0)

18 (94.7)

40 (90.9)

Grade 3/4 TRAE

6 (24.0)

4 (21.1)

10 (22.7)

Serious TRAE

0

2 (10.5)

2 (4.5)

Death due to TRAE

0

0

0

Discontinuation due to TRAE

1 (4.0)

2 (10.5)

3 (6.8)

Discontinuation due to treatment-related SAE

0

1 (5.3)

1 (2.3)

DLTs

3 (12.0)

1 (5.3)

4 (9.1)

Table 1. Summary of Treatment-Related Adverse Events.DLTs indicates dose-limiting toxicities; SAE, serious AE; TRAE, treatment-related adverse event.

n (%)

MK-5890 (n = 25)

MK-5890 + pembrolizumab (n = 19)

MK-5890 + pembrolizumab, crossover n = 14

Objective response (CR + PR)

1 (4.0)

2 (10.5)

5 (35.7)

CR

0

0

2 (14.3)

PR

1 (4.0)

2 (10.5)

3 (21.4)

SD

5 (20.0)

7 (36.8)

1 (7.1)

DCR (CR + PR + SD≥12 months)

2 (8.0)

2 (10.5)

5 (35.7)

PD

16 (64.0)

7 (36.8)

6 (42.9)

No assessment

3 (12.0)

3 (15.8)

2 (14.3)

Table 2. Summary of Best Overall Response.CR indicates complete response; DCR, durable complete response; PD, progressive disease; PR, partial response; SD, stable disease.

References

1. Shapira-Frommer R, van Dongen MGJ, Dobrenkov K, et al. Phase 1 study of an anti-CD27 agonist as monotherapy and in combination with pembrolizumab in patients with advanced solid tumors. Presented at: 34th Annual Meeting & Pre-Conference Programs of the Society for Immunotherapy of Cancer (SITC 2019). November 7-10, 2019. National Harbor, MD.
2. Hendriks J, Xiao Y, Borst J. CD27 promotes survival of activated T cells and complements CD28 in generation and establishment of the effector T cell pool.J Exp Med. 2003;198(9):1369-1380. doi: 10.1084/jem.20030916.