Etigilimab plus Nivolumab shows tolerability in advanced solid tumors

Observed tolerability and potential efficacy of etigilimab (MPH313) and nivolumab (Opdivo) in patients with relapsed or advanced solid tumors and in patients with PD-L1-low disease, based on an update to the selected cohort of the Phase 1b/2 ACTIVATE study (NCT04761198). exist 2023 European Society for Medical Oncology Congress (ESMO).

As of the data cutoff of March 29, 2023, the objective response rate (ORR) was 25% in a total of 40 patients receiving combination therapy, including checkpoint inhibitor-naïve endometrial cancer (n = 10), cervical cancer Cohorts of patients with carcinoma (n = 8), uveal melanoma (n = 8), dedifferentiated liposarcoma (n = 10), and germ cell tumors (n = 4).

The only complete responses (CR) in the cervical cancer cohort occurred in 3 patients who received treatment for a median of 12.5 months. Partial responses (PR) were reported in the endometrium (n = 3), uveal melanoma (n = 2), dedifferentiated liposarcoma (n = 1), and germ cell tumor (n = 1) cohorts, a total of 7 patients PR; These patients had been on treatment for a median of 12.0 months. Additionally, 11 patients had stable disease (SD) and 19 patients had progressive disease. The median duration of treatment for SD patients was 6.25 months. 1

“Some SD patients do have tumors that shrink, and some of those PRs are deep responses,” explains Meredith Mckean, MD, MPH, director of the Melanoma and Skin Cancer Research Program at the Sarah Cannon Institute in Nashville, Tennessee. “Swimmers The plot (shows) that these responses are very durable; “At the time of the data cutoff, there were many patients still on treatment, and even SD patients were still on the study for a while. “

A large number of patients who responded to etigilimab treatment had PD-L1-low disease. Six of the seven patients who had been treated for at least 11 months had PD-L1-negative or PD-1-low disease, and all seven had high PVR tumor expression.

In addition to low PD-L1 status, biomarkers were also of interest in this study, Mckean noted, “A correlation was observed with positive co-expression of CD226 and CD8 in patients with objective responses, particularly in cervical cancer and This may be useful as a future biomarker in uveal melanoma.” Strong target engagement was also found, including sustained activation of T cell subsets and a reduction in Tregs – with total CD8 T cell frequencies remaining stable.

The ACTIVATE trial enrolled 72 patients with advanced or metastatic solid tumors for whom there were no available treatments or standard of care therapies. Cervical cancer (n = 8), endometrial cancer (n = 10), ovarian cancer (n = 10), germ cell tumor (n = 6), sarcoma (n = 16), including dedifferentiated liposarcoma and undifferentiated The pleomorphic sarcoma and uveal melanoma (n = 8) cohort had not previously received checkpoint inhibitors. Patients in the high tumor mutation burden and microsatellite stable (n = 9) and endometrial cancer (n = 5) cohorts may have previously received checkpoint inhibitors.

Mckean noted that the tumor types were chosen “because of their known high expression of TGIT and PVR and co-expression of TGIT and PD-1. Notably, several of these tumor types are known to be less responsive to anti-PD-1 monotherapy.” .”

The combination of etigilimab and nivolumab was well tolerated, and no new safety signals were observed during the study. In the safety population (n = 76), serious treatment-emergent adverse events (TEAEs) occurred in 28.9% of patients, and grade 3 or higher TEAEs occurred in 40.8% of patients.

Treatment-related AEs (TRAEs) of any grade were more commonly attributed to nivolumab (72.4%) than etekizumab (68.4%), and were also attributed to the combination (65.8%). The most common TRAEs of any grade included rash (42.1%), gastrointestinal including nausea and diarrhea (27.6%), and general symptoms (26.3%). In addition, 6 patients experienced grade 1 to 2 infusion reactions.

Grade 3 or higher TRAEs occurred in 11.8% of patients and included type 1 diabetes, maculopapular rash, hepatobiliary disease, pneumonia, hematemesis, immune-mediated gastritis, transaminitis, decreased neutrophil count, and adrenal insufficiency. Additionally, 4 patients discontinued treatment due to TRAEs. No treatment-related deaths were reported. 1

Enrolled patients were 18 years of age or older and had a combined PD-L1 positive score of at least 1% in the cervical cancer cohort. Patients with HIV infection or active hepatitis B or C were not included in the study. The primary endpoint of the study is investigator-assessed ORR according to RECIST 1.1, and secondary endpoints include duration of response and safety.

Intravenous (IV) etigilimab every 2 weeks and nivolumab 240 mg IV every 2 weeks. Etigilimab is an IgG1 antibody that binds to Fc receptors and promotes myeloid cell activation and antibody-dependent cellular cytotoxicity.

Mckean explained that etigilimab “clearly differs from Fc receptor silencing antibodies in that it reduces Tregs and promotes myeloid cell activation. It differs from Fc receptor antibodies in that it significantly reduces Tregs by optimizing affinity while total CD8 frequency remains constant, thus Preserve immune cells to enhance tumor cell killing and achieve optimal safety.”

The last dose of etigilimab was administered on June 26, 2023, and ACTIVATE is now complete. The researchers noted that the cervical cancer and uveal melanoma cohorts had passed the Simon Phase 2 design interim futility surveillance criteria for expansion into Phase 2—the cohort also received expansion approval from the independent data monitoring committee. However, while Mckean noted that endometrial cancer, dedifferentiated liposarcoma and germ cell tumor cohorts that did not receive checkpoint inhibitors have not yet been formally evaluated for futility, they may show promise.

refer to

Mckean M, Dumbrava EE, Hamid O, et al. Safety and efficacy of etigilimab (anti-TIGIT) combined with nivolumab (anti-PD1) in the treatment of relapsed/advanced solid tumors. Ann Anker. 2023;34(Supplement 2):S621-S622. doi:10.1016/j.annonc.2023.09.2160