Cobolimab/Dostarlimab Combination Shows Initial Efficacy and Safety Signals in Advanced NSCLC

Diwakar Davar, MD, MSc

The anti–TIM-3 monoclonal antibody, cobolimab (TSR-022/GSK4069889), utilized in combination with the anti–PD-1 antibody dostarlimab-gxly (Jemperli) demonstrated promising signs of clinical activity and an acceptable safety profile across all dose levels in heavily pretreated patients with advanced/metastatic non–small cell lung cancer (NSCLC), according to data from the phase 1 AMBER trial (NCT02817633) presented at the 2023 SITC Annual Meeting.

Among the 84 patients in the total study population, cobolimab plus dostarlimab elicited an overall response rate (ORR) of 8.3% (95% CI, 3.4%-16.4%) and a disease control rate (DCR) was 21.4% (95% CI, 13.2%-31.7%). Moreover, the immune-related ORR (irORR) with the combination was 9.5% (95% CI, 4.2%-17.9%) and the immune-related DCR (irDCR) was 25% (95% CI, 15.2%-35.6%). These responses translated into progression free survival (PFS) and overall survival (OS) benefits.

The median PFS for the 100 mg (n = 14), 300 mg (n = 21), and 900 mg (n = 29) dosing levels were 1.9 months (95% CI, 0.8-3.4), 2.1 months (95% CI, 1.9-3.8), and 2.1 months (95% CI, 1.9-2.2), respectively. The median OS for each respective dose levels was 11.6 months (95% CI, 2.8-not evaluable), 6.2 months (95% CI, 4.1-12.9), and 9.0 months (95% CI, 3.7-14.7).

“Based on the findings shown here, and previously reported receptor occupancy, safety [no dose limiting toxicities], pharmacokinetics, pharmacodynamics, and efficacy, 30 mg [of] cobolimab in combination with dostarlimab was confirmed to be the recommended phase 2 dose,” Diwakar Davar, MD, MSc, stated in a presentation of the data. Davar is an assistant professor of medicine and a medical oncologist/hematologist in the Department of Hematology Oncology/Medical Oncology at the University of Pittsburgh Medical Center (UPMC), UPMC Hillman Cancer Center, Pennsylvania.

When exposed to cognate antigens, TIM-3 is upregulated on the surface of T cells and other cellular compartments, causing cellular dysfunction, Davar noted during the presentation of data. He adds that cells expressing TIM-3 exhibit more dysfunction than TIM-3–negative T cells. Furthermore, preclinical studies have suggested that dual blockade, particularly with cobolimab, enhances T cell function.

The anti-TIM-3 monoclonal antibody cobolimab binds to TIM-3, boosting T cell activity in ex vivo T-cell stimulation assays. Preclinical studies have demonstrated that dual blockade of TIM-3 and PD-1 improves T cell activity and inhibits tumor cell growth, he explained.

Based on these data, investigators launched the 2-part, multicenter, open-label AMBER trial assessed the safety and efficacy of cobolimab as a monotherapy and in combination regimens for patients with advanced solid tumors. Part 2b of the trial evaluated the combination of dostarlimab and cobolimab at various dose levels in heavily pretreated patients with NSCLC.

Patients 18 years of age or older with advanced, pretreated metastatic NSCLC whose disease had progressed on prior anti–PD-(L)1 therapy were eligible for enrollment onto the study, as were patients who had previously received an EGFR TKI or an ALK inhibitor for treatment of a known mutation.

Upon enrollment, patients were intravenously administered 1 of 3 dosing regimens: 100 mg of cobolimab and 500 mg of IV dostarlimab 3 times a week; 300 mg of cobolimab and 500 mg of dostarlimab 3 times a week; or 900 mg of intravenous cobolimab and 500 mg of intravenous dostarlimab 3 times a week. Patients received treatment until disease progression.

Safety follow-ups were performed at 30 and 90 days after the end of treatment or initiation of a new anticancer therapy. Additionally, radiographic evaluations were also conducted at screening every 8 weeks after the initial dose, as well as at every 12 weeks after 1 year of treatment. Notably, responses were assessed by investigators per RECIST v1.1 criteria or irRECIST criteria for immune-related end points and the data cut-off for evaluation was February 2023.

The primary end point of the study was ORR, while secondary end points included DCR, irDCR, irORR, PFS, OS, and safety. Exploratory end points included post-hoc biomarker assessments. These efficacy and safety analyses were performed using the safety population, which consisted of any patient who received any amount of the study drug.

The median age of patients enrolled across all cohorts was 65.9 years (range, 35-86) and a majority of patients were White (86.9%), not Hispanic or Latino (84.5%), and male (59.5%). Patients had an ECOG performance status of 0 (19%) or 1 (81%) and either adenocarcinoma (69.0%) or squamous cell (26.2%) histology. Notably, patients had 1 (10.7%), 2 (31.0%), 3 (17.9%), 4 (16.7%), and 5 or more (23.8%) prior lines of treatment.

Notably, patients had a PD-L1 Tumor Proportion Score of less than 1% (32.1%), 1% to 49% (21.4%), and 50% or more (20.2%), and 4.8% of patients had a known EGFR mutation.

ORRs were 7.1% (95% CI, 0.2%-33.9%), 9.8% (95% CI, 2.7%-23.1%), and 6.9% (95% CI, 0.8%-22.8%) across the 100 mg, 300 mg and 900 mg treatment cohorts, respectively. The DCR in each respective cohort was 21.4% (95% CI,3.7%-50.8%), 22.0% (95% CI, 10.6%-37.6%), and 20.7% (95% CI, 8.0%-39.7%). Partial response (PR) rates were 7.1%, 9.8%, and 6.9%; 14.3%, 12.2%, and 13.8% of patients achieved stable disease (SD); and the rate of progressive disease (PD) was 57.1%, 56.1%, and 51.7%, respectively.

Furthermore, the irORR in the 100 mg, 300 mg and 900 mg cohorts was 7.1% (95% CI, 0.2%-33.9%), 12.2% (95% CI, 4.1%-26.2%), and 6.9% (95% CI, 0.8%-22.8%); the irDCR was 21.4% (95% CI, 4.7%-50.8%), 26.8% (95% CI, 14.2%-42.9%), and 24.1% (95% CI, 10.3%-43.5%); the irPR was 7.1%, 12.2%, and 6.9%; the irSD was 14.3%, 14.6%, and 17.2%; and the irPD was 57.1%, 48.8%, and 48.3%.

“Patients with either a PR or SD and patients with either irPR or irSD had higher TIM-3 immunohistochemistry levels vs patients with PD or patients with irPD, respectively,” Davar said.

Looking to safety across the total patient population, 98.8% of patients experienced a treatment-emergent adverse event (TEAE), 54.8% of which was grade 3 or higher. Additionally, 52.4% of patients experienced a treatment-related AE (TRAE), 13.1% of which were grade 3 or higher. Treatment-emergent serious AEs (TESAE) occurred in 45.2% of patients.

The most common TEASEs experienced by patients were pneumonia (8.3%), back pain (4.8%), atrial fibrillation (3.6%), dyspnea (3.6%), hypoxia (3.6%), pleural effusion (3.6%), and respiratory failure (3.6%). Six percent of TEAEs led to treatment discontinuation, 21.4% led to study treatment delay, and 4.8% were fatal. No fatal TRAEs were observed.

Davar concluded the presentation by highlighting the ongoing phase 2/3 COSTAR trial (NCT04655976). The study is comparing the combination of cobolimab, dostarlimab, and docetaxel with dostarlimab plus docetaxel, and docetaxel alone in patients with relapsed/refractory advanced NSCLC who received prior PD-(L)1 thereapy.

Reference

Davar D, Eroglu Z, Milhem M, et al. AMBER, Part 2B: a Phase 1 study of cobolimab plus dostarlimab in patients with advanced/metastatic non-small cell lung cancer (NSCLC) previously treated with anti-PD(L)-1 therapy. Presented at: 2023 SITC Annual Meeting; November 1-5, 2023; San Diego, CA. Abstract 596.