Cobolimab Plus Dostarlimab Achieves Clinical Responses in Advanced Melanoma

Treatment with the combination of cobolimab and dostarlimab (Jemperli) led to an overall objective response rate (ORR) and immune-related ORR of 42.9% (n = 12/28) consisting of all partial responses (PRs) in patients with advanced or metastatic melanoma, according to data from the phase 1 AMBER study (NCT02817633) presented at the 2022 ASCO Annual Meeting.

“Cobolimab plus dostarlimab showed preliminary antitumor activity, supporting the rationale for dual TIM-3 and PD-1 blockade in advanced or metastatic solid tumors,” lead study author Antoni Ribas, MD, PhD, of the University of California, Los Angeles, said in a presentation of the data.

TIM-3 is an immune checkpoint receptor that is associated with inhibitory antitumor responses, but concurrent TIM-3 and PD-1 blockade is more effective at reducing tumor growth than either pathway alone. Cobolimab is a selective anti–TIM-3 monoclonal antibody that activates immune cell function and induces substantial antitumor activity in combination with anti–PD-1 agents like dostarlimab.

As such, investigators evaluated the safety of cobolimab plus dostarlimab in patients with metastatic solid tumors (parts 1 and 2) and efficacy in patients with advanced or metastatic melanoma (parts 1C and 1E).

The open-label, multicenter study was split into 2 parts: a dose-escalation (part 1 A-H) and -expansion (part 2 A-D) phase.

To be eligible for enrollment, patients had to be at least 18 years of age and have an ECOG performance status of 0 or 1. In part 1C, patients had to have advanced or metastatic solid tumors, including immunotherapy-naïve melanoma and disease progression on or intolerance to prior therapy. In part 1E, patients had to have advanced or metastatic immunotherapy-naïve melanoma with or without prior treatment.

Key exclusion criteria included a history of grade 3 or greater immune-related adverse effects (AEs) with prior immunotherapy and active autoimmune disease requiring systemic therapy. In part 1E, the 300-mg or higher dose levels for dostarlimab excluded patients with uveal melanoma.

In part 1C (n = 10), patients received 1 of 3 doses of intravenous (IV) cobolimab: 100 mg, 300 mg, or 900 mg plus 500 mg of IV dostarlimab. In part 1E (n = 18), patients received either 300 mg or 900 mg of IV cobolimab plus 500 mg of IV dostarlimab.

Parts 1A through C evaluated the efficacy and safety of cobolimab as a single agent and in combination with dostarlimab or nivolumab (Opdivo) in patients with advanced or metastatic solid tumors.

Treatment was continued every 3 weeks until disease progression, unacceptable toxicity, withdrawal of consent, or death for up to 2 years.

The primary end points in part 1C were safety and tolerability, as well as to identify the recommended phase 2 dose (RP2D) for the regimen. In part 1E, the primary end point was the ORR including PRs and complete responses (CRs) per RECIST v1.1 criteria.

The secondary end point in part 1C was the ORR per RECIST v1.1 criteria. Exploratory end points in both cohorts included the disease control rate (DCR) including stable disease for at least 16 weeks, PR or CR per RECIST v1.1 criteria, and ORR and DCR per immune-related RECIST criteria.

Additional results showed that at the RP2D of 300 mg of cobolimab and 500 mg of dostarlimab, the ORR was 57.1% (n = 8/14).

In this population, the median patient age was 66.0 years (range, 30.0-90.0), and most patients were male (n = 162/273; 59.3%), Caucasian (n = 238/273; 87.2%), and had an ECOG PS of 1 (n = 171/273; 62.6%). In parts 1C and 1E, most patients had cutaneous melanoma (82.1%) and an ECOG performance status of 0 (67.9%).

“Cobolimab in combination with dostarlimab had a manageable safety profile, with no new toxicities identified, in an integrated safety analysis that included 273 patients with advanced or metastatic solid tumors,” Ribas said.

Any-grade and grade 3 or greater treatment-related treatment-emergent adverse effects (TR-TEAEs) occurred in 57.4% (n = 159) and 13.4% (n = 37) of patients, respectively. The most common any-grade TR-TEAEs were fatigue (n = 48; 17.3%), rash (n = 21; 7.6%), diarrhea (n = 19; 6.9%), and dyspnea (n = 8; 2.9%). Serious TR-TEAEs and TR-TEAEs leading to discontinuation occurred in 8.7% (n = 24) and 4.7% (n = 13) of patients, respectively.

In the target-dose cohort (n = 167), the incidences were lower with regard to fatigue (n = 22; 13.2%), rash (n = 9; 5.4%), diarrhea (n = 10; 6.0%), and dyspnea (n = 0). Additionally, any-grade and grade 3 or greater TR-TEAEs occurred in 57.5% (n = 96) and 10.8% (n = 18) of patients, respectively. Serious TR-TEAEs and TR-TEAEs leading to discontinuation occurred in 7.8% (n = 13) and 4.2% (n = 7) of patients in this cohort, respectively.

Ongoing research with the agent includes the randomized phase 2 COSTAR trial (NCT04655976), which is evaluating cobolimab plus dostarlimab and docetaxel vs docetaxel alone in relapsed/refractory non–small cell lung cancer following PD-1/PD-L1 inhibition, and a phase 2 study (NCT04139902) evaluating neoadjuvant cobolimab plus dostarlimab vs dostarlimab alone in high-risk, resectable melanoma.

Reference

1. Ribas A, Eroglu Z, Trigo Perez JMM, et al. AMBER parts 1c and 1e: A phase 1 study of cobolimab plus dostarlimab in patients (pts) with advanced/metastatic melanoma. J Clin Oncol. 2022;40(suppl 16):9513. doi:10.1200/JCO.2022.40.16_suppl.9513