T cell Immunoglobulin and Mucin Domain Containing Protein 3 (TIM-3) Inhibitors in Oncology Clinical Trials: A Review.

T cell immunoglobulin and mucin domain containing protein 3 (TIM-3) is a receptor found on a multitude of immune cells and is commonly overexpressed in patients with cancer. Due to its selective expression in immune cells and its preliminary efficacy in preclinical models, TIM-3 is a promising target as a treatment for cancer. Both monotherapy and combination regimens are being developed and are currently under investigation. This clinical review seeks to summarize and compile past, present, and future TIM-3 inhibitors in clinical trials.

A phase 2 study of AZD4635 in combination with durvalumab or oleclumab in patients with metastatic castration-resistant prostate cancer.

BACKGROUND: Inhibition of the adenosine 2A receptor (A2AR) diminishes the immunosuppressive effects of adenosine and may complement immune-targeting drugs. This phase 2 study evaluated the A2AR antagonist AZD4635 in combination with durvalumab or oleclumab in patients with metastatic castration-resistant prostate cancer. METHODS: Patients with histologically/cytologically confirmed disease progressing within 6 months on ≥ 2 therapy lines were randomly assigned to either Module 1 (AZD4635 + durvalumab) or Module 2 (AZD4635 + oleclumab). Primary endpoints were objective response rate per RECIST v1.1 and prostate-specific antigen (PSA) response rate. Secondary endpoints included radiological progression-free survival (rPFS), overall survival, safety, and pharmacokinetics. RESULTS: Fifty-nine patients were treated (Module 1, n = 29; Module 2, n = 30). Median number of prior therapies was 4. One confirmed complete response by RECIST (Module 1) and 2 confirmed PSA responses (1 per module) were observed. The most frequent adverse events (AEs) possibly related to AZD4635 were nausea (37.9%), fatigue (20.7%), and decreased appetite (17.2%) in Module 1; nausea (50%), fatigue (30%), and vomiting (23.3%) in Module 2. No dose-limiting toxicities or treatment-related serious AEs were observed. In Module 1, AZD4635 geometric mean trough concentration was 124.9 ng/mL (geometric CV% 69.84; n = 22); exposures were similar in Module 2. In Modules 1 and 2, median (95% CI) rPFS was 2.3 (1.6 -3.8) and 1.5 (1.3- 4.0) months, respectively. Median PFS was 1.7 versus 2.3 months for patients with high versus low blood-based adenosine signature. CONCLUSION: In this heavily pretreated population, AZD4635 with durvalumab or oleclumab demonstrated minimal antitumor activity with a manageable safety profile. CLINICAL TRIAL: gov identifier: NCT04089553.

B7-H3 Inhibitors in Oncology Clinical Trials: A Review.

B7-H3 is a transmembrane receptor highly prevalent on malignant cells and plays an important role in adaptive immunity that is not fully elucidated. Targeted B7-H3 inhibitors, including antibody-drug conjugates, radioimmunotherapy, and monoclonal antibodies, are a new class of antineoplastic agents showing promising preliminary clinical efficacy, observed with several of these agents against multiple tumor types. Particularly promising treatments are enoblituzumab for prostate cancer, 131I-omburtamab for central nervous system malignancies, and HS-20093 for small-cell lung cancer but further studies are warranted. There are clinical trials on the horizon that have not yet enrolled patients examining chimeric antigen receptor T-cell therapies, bi- and tri-specific killer engagers, and dual-affinity retargeting proteins. These data will be telling of the efficacy of B7-H3 inhibitors in both hematologic and solid malignancies. This study aimed to compile available results of B7-H3 inhibitors in oncology clinical trials.

Sotorasib with panitumumab in chemotherapy-refractory KRASG12C-mutated colorectal cancer: a phase 1b trial.

The current third-line (and beyond) treatment options for RAS-mutant metastatic colorectal cancer have yielded limited efficacy. At the time of study start, the combination of sotorasib, a KRAS (Kirsten rat sarcoma viral oncogene homolog)-G12C inhibitor, and panitumumab, an epidermal growth factor receptor (EGFR) inhibitor, was hypothesized to overcome treatment-induced resistance. This phase 1b substudy of the CodeBreaK 101 master protocol evaluated sotorasib plus panitumumab in patients with chemotherapy-refractory KRASG12C-mutated metastatic colorectal cancer. Here, we report the results in a dose-exploration cohort and a dose-expansion cohort. Patients received sotorasib (960 mg, once daily) plus panitumumab (6 mg kg-1, once every 2 weeks). The primary endpoints were safety and tolerability. Secondary endpoints included efficacy and pharmacokinetics. Exploratory biomarkers at baseline were assessed. Forty-eight patients (dose-exploration cohort, n = 8; dose-expansion cohort, n = 40) were treated. Treatment-related adverse events of any grade and grade ≥3 occurred in 45 (94%) and 13 (27%) patients, respectively. In the dose-expansion cohort, the confirmed objective response rate was 30.0% (95% confidence interval (CI) 16.6%, 46.5%). Median progression-free survival was 5.7 months (95% CI 4.2, 7.7 months). Median overall survival was 15.2 months (95% CI 12.5 months, not estimable). Prevalent genomic coalterations included APC (84%), TP53 (74%), SMAD4 (33%), PIK3CA (28%) and EGFR (26%). Sotorasib-panitumumab demonstrated acceptable safety with promising efficacy in chemotherapy-refractory KRASG12C-mutated metastatic colorectal cancer. ClinicalTrials.gov identifier: NCT04185883 .