Background T-cell immunoglobulin- and mucin-domain-containing-3 (TIM-3) expression on tumor-infiltrating lymphocytes and myeloid-derived cells is associated with immune exhaustion and poor prognosis in patients with NSCLC.^{1 2} Cobolimab, an anti-TIM-3 monoclonal antibody, in combination with dostarlimab (a PD-1 inhibitor), has been shown to enhance T-cell activity in preclinical assessments.³

Objectives To assess the safety and efficacy of cobolimab plus dostarlimab in patients with advanced/metastatic NSCLC.

Methods AMBER (NCT02817633) is a dose escalation and expansion, multicenter, open-label, Phase 1 study assessing cobolimab monotherapy and combinations in patients with advanced solid tumors. AMBER part 2B tested cobolimab and dostarlimab combination in patients with advanced/metastatic NSCLC previously treated with anti-PD(L)-1 therapy. Eligible patients received cobolimab (100, 300, or 900 mg IV) plus dostarlimab (500 mg IV) Q3W. The primary endpoint included objective response rate (ORR) per RECIST v1.1; secondary endpoints included disease control rate (DCR), immune-related (ir)-ORR and irDCR per irRECIST, overall survival (OS), and safety; exploratory endpoints included biomarker assessments (post hoc).

Results Eighty-four patients were treated (mean age 65.9 years [range: 35–86]). The most common histologies were adenocarcinoma (69.0%) and squamous cell (26.2%), and 58.3% of patients had ≥3 prior treatment lines. At data cut-off (February 2023), across all doses, ORR was 8.3%, irORR was 9.5%, DCR was 21.4%, and irDCR was 25.0% (table 1). The highest ORR (9.8%) was observed in the cobolimab 300 mg cohort, which was ultimately selected as the recommended Phase 2 dose. Patients with irRECIST defined partial response or stable disease (n=12) had higher baseline TIM-3 immunohistochemistry (research use only assay) levels versus patients with progressive disease (n=22; p=0.013); a similar trend was observed for ORR. Patients with lower than median baseline systemic interleukin (IL)-6 and IL-8 correlated with a higher OS versus patients with higher than median baseline systemic IL-6 and IL-8 (table 2).

Treatment-emergent adverse events (TEAEs) ≥1 occurred in 98.8% of patients, most commonly: fatigue (42.9%), dyspnea (31.0%), and decreased appetite (27.4%); 54.8% of patients had Grade ≥3 TEAEs. In total, 52.4%, 13.1%, and 7.1% of patients had treatment-related adverse events (TRAEs), Grade ≥3 TRAEs, and serious TRAEs respectively; no TRAEs deaths were observed.

Conclusions Cobolimab plus dostarlimab showed early evidence of efficacy and acceptable safety in patients with advanced/metastatic NSCLC. Cobolimab plus dostarlimab and docetaxel versus standard of care is being evaluated in COSTAR, an ongoing Phase 2/3 study (NCT04655976) for patients with advanced NSCLC.

Acknowledgements The authors would like to thank the patients and their families for consenting to the study and analysis, the study coordinators and operations team in facilitating the study, and acknowledge Hasan H Jamal at GSK for their review and coordination of the abstract. Medical writing support was provided by Nicholas Thomas, at Fishawack Indicia, UK, part of Fishawack Health Ltd, and funded by GSK (213348; NCT02817633)..

Trial Registration NCT02817633

References

1. Das M,Zhu C, Kuchroo VK. Tim-3 and its role in regulating anti-tumor immunity. Immunol Rev. 2017; 276(1): 97–111.

2. Zhang C, Xu L, Ma Y, Zhou L, Le H, Chen Z. Increased TIM-3 expression in tumour-associated macrophages predicts a poorer prognosis in non-small cell lung cancer: a retrospective cohort study. J Thoracic Disease. 2023; 15(3): 1433–1444.

3. Sakuishi K, Apetoh L, Sullivan JM, Blazar BR, Kuchroo VK, Anderson AC. Targeting Tim-3 and PD-1 pathways to reverse T cell exhaustion and restore anti-tumor immunity. J Exp Med. 2010; 207(10): 2187–2194.

Ethics Approval The study was approved by respective IRB/IEC/Competent authorities prior to approval (GSK study 213348).