Phase 1 trial of TIM-3 inhibitor cobolimab monotherapy and in combination with PD-1 inhibitors nivolumab or dostarlimab (AMBER).

Abstract

2504 Background: TIM-3 expressed on tumor-infiltrating T cells is associated with T-cell suppression. AMBER (NCT02817633) is evaluating cobolimab (TSR-022/GSK4069889) monotherapy and with PD-1 inhibitors in advanced solid tumors. Methods: Multi-center, open-label study conducted with the following escalation arm (Parts 1A–C primary analysis reported here): (1A) cobolimab (IV Q2W) monotherapy at 7 doses (6 weight-based [0.03–10 mg/kg] and 1 flat [1200 mg] dose); (1B) cobolimab (1 mg/kg) + nivolumab (3 mg/kg IV Q2W); and (1C) cobolimab (100, 300, or 900 mg) + dostarlimab (500 mg IV Q3W). Primary endpoints were safety, tolerability, and recommended phase 2 dose (RP2D, monotherapy and combination). Results: 104 patients (pts) were included: 1A (n=46), 1B (n=7), or 1C (n=55); 4 pts from 1A crossed over to 1C (included in 1A and 1C safety and efficacy analyses). Most common cancers were non-small cell lung cancer (NSCLC) and melanoma (1A), NSCLC (1B), and NSCLC, skin, and peritoneal mesothelioma (1C). In 1A, 30.4% had ≥5 lines (L) of prior therapy; 42.9% had 3L in 1B; 33.3% had 2L in 1C. Treatment-related treatment-emergent adverse events (TR-TEAE) occurred in 67.4% (1A), 85.7% (1B), and 67.3% (1C); most commonly in 1A (n≥4) fatigue (13.0%) and nausea (8.7%); 1B (n≥3) diarrhea (57.1%) and nausea and vomiting (42.9% each); and 1C (n≥8) fatigue (20.0%) and rash (14.5%). Grade (Gr)≥3 TR-TEAEs occurred in 4.3% (1A), 28.6% (1B), and 14.5% (1C). There were no Gr5 TR-TEAEs or TR-TEAEs leading to dose delay. Serious TR-TEAEs occurred in 2.2% (1A), 0% (1B), and 12.7% (1C). TR-TEAEs led to discontinuation in 2.2% (1A), 28.6% (1B), and 9.0% (1C). Dose limiting toxicities (DLTs) occurred in 3.0% (1/33) in 1A (Gr3 lipase increased [10 mg/kg]); 40.0% (2/5) in 1B (Gr3 diarrhea and ALT and AST elevation); and 0% in 1C. Cobolimab serum exposure increased in a dose proportional manner at the therapeutic dose range. Preliminary mean terminal phase t1/2 ranged from 2.5–5.8 days for 0.03–0.3 mg/kg and 6.9–10.2 days for 1–10 mg/kg doses (1A), 6.9 days for 1B, and 9.5–12.3 days for 1C. Conclusions: Cobolimab + dostarlimab was well tolerated and showed preliminary anti-tumor activity, warranting further investigation of the RP2D + docetaxel in a randomized, phase 2 study. Funding: GSK (213348). Clinical trial information: NCT02817633. [Table: see text]

Combinatorial blockade for cancer immunotherapy: targeting emerging immune checkpoint receptors

“…A phase I/II trial (NCT02608268) evaluated MGB453 (anti-TIM3) in combination with PDR001 (anti-PD-1) in advanced solid cancers such as melanoma and NSCLC and showed excellent safety profile and preliminary antitumor activity ( 170 ). Similar encouraging results were shown by trials (NCT02817633 and NCT03680508) that evaluated TSR-022 (anti-TIM3) in combination with PD-1 inhibitors ( 171 , 172 ). In addition, a phase Ia/b trial evaluated the safety, pharmacokinetics, and efficacy of LY3321367 (anti-TIM3) plus LY3300054 (Anti-PD-L1) and showed modest antitumor activity ( 173 ).…”

Targeting LAG-3, TIM-3, and TIGIT for cancer immunotherapy

“…Similarly, different anti-TIM-3 mAbs combined with anti-PD-1 mAbs in the treatment of advanced lymphomas or NSCLC displayed higher efficacy than TIM-3 blockers alone (objective response rate (ORR): 42.9% vs. 0%; disease control rate (DCR): 42.9% vs. 11.1%) [ 167 ]. At the ASCO-SITC Clinical Immuno-Oncology Symposium of 2019, it was shown that in a Phase I a/b trial, the efficacy of LY3321367, an anti-TIM-3 mAb, in patients with NSCLC varied depending on the anti-PD-1/L1 efficacy; that is, the efficacy in anti-PD-1/L1 refractory patients ( N = 23, ORR: 0%, DCR: 35%, PFS: 1.9 months) was compared to that in anti-PD-1/L1 responders ( N = 14, ORR: 7%, DCR: 50%, PFS: 7.3 months).…”

Developments and future prospects of personalized medicine in head and neck squamous cell carcinoma diagnoses and treatments

“…Combining GSK3359609 with pembrolizumab demonstrated promising anti‐tumor activity in patients with anti‐PD‐1/PD‐L1‐naïve HNSCC 135 . Furthermore, other co‐stimulator/co‐inhibitor targets, such as TIM‐3 and KIR, combined with anti‐PD‐1 therapy, are also being explored in various advanced solid tumors 136 . Personalized treatment approaches for HNSCC are focusing on targeting specific immune‐related pathways and combining various immunotherapies to increase anti‐tumor responses and provide a better patient outcome.…”