Phase 1 Study of INBRX-105, a TNFRSF9 (4-1BB) and PD-L1 Bispecific Antibody, in Patients with Select Solid Tumors
Jong Chul Park1, David Berz2, Manish R Sharma3
1Massachusetts General Hospital , Boston, Massachusetts.
Purpose:
INBRX-105, a tetravalent, PD-L1-targeted TNFRSF9 (4-1BB) agonist, demonstrated preclinical antitumor activity. This first-in-human study evaluated INBRX-105 in solid tumors.
Patients And Methods:
This open-label, 4-part, phase 1 study evaluated INBRX-105 alone or with pembrolizumab in adults with locally advanced/metastatic, unresectable solid tumors (NCT03809624). INBRX-105 was administered intravenously once every 2 weeks or 4 weeks in parts 1 (single-agent dose escalation; 0.001-3 mg/kg) and 2 (single-agent expansion) or once every 3 weeks in parts 3 (combination dose escalation; INBRX-105 0.03-1.0 mg/kg) and 4 (combination expansion). Part 2 enrolled patients with checkpoint inhibitor-relapsed/refractory (CPI-R/R) tumors. Part 4 enrolled patients with CPI-R/R or CPI-naïve disease. The primary endpoint was safety and tolerability of INBRX-105. Preliminary clinical response was a secondary endpoint.
Results:
Of 160 patients assessed, 81 received monotherapy (median age, 65 years; female, 50.6%), and 79 combination therapy (median age, 64 years; female, 38%). The INBRX-105 maximum tolerated dose was 0.3 mg/kg once every 3 weeks. Head and neck squamous cell carcinoma (n = 61) and non-small cell lung cancer (n = 25) were the most common tumor types. The most common any-grade INBRX-105-related adverse events (AE) were fatigue (monotherapy, 35.8%; combination, 17.7%), increased aspartate aminotransferase (25.9%; 15.2%), and nausea (19.8%; 17.7%). INBRX-105-related hepatic AEs occurred in 41 patients [monotherapy, n = 25 (grade ≥3, n = 11); combination, n = 16 (grade ≥3, n = 6)]. In all patients, the objective response rate was 8.8% [monotherapy, 3.7%; combination, 13.9% (CPI-naïve, 30%; CPI-R/R, 8.6%)]; the disease control rate was 43.1%.
Conclusions:
The low response rates and hepatic safety signals observed do not support further clinical development of INBRX-105.
Significance:
Tumor resistance to CPIs often develops, underscoring an unmet need. This first-in-human phase 1 trial evaluated INBRX-105-a tetravalent, PD-L1-targeted 4-1BB agonist-alone or with pembrolizumab. Unfortunately, clinical development of INBRX-105 was ended because of hepatotoxicity and limited efficacy. Novel treatment combinations with nonredundant, complementary immunotherapies are needed.
Insights
INBRX-105, a novel immunotherapy, showed limited efficacy and concerning liver toxicity in solid tumors. Further clinical development was halted due to these safety and response rate issues.
Area of Science:
- Immunotherapy
- Oncology
- Pharmacology
Background:
- Checkpoint inhibitors (CPIs) are crucial in cancer therapy, but tumor resistance necessitates novel treatment strategies.
- INBRX-105 is a tetravalent agonist targeting PD-L1 and TNFRSF9 (4-1BB), designed to enhance anti-tumor immunity.
- This study addresses the unmet need for effective treatments in patients with advanced solid tumors, particularly those resistant to CPIs.
Purpose of the Study:
- To evaluate the safety, tolerability, and preliminary efficacy of INBRX-105 as a monotherapy and in combination with pembrolizumab in patients with advanced solid tumors.
- To determine the maximum tolerated dose (MTD) of INBRX-105 in this patient population.
Main Methods:
- A Phase 1, open-label, four-part study (NCT03809624) involving adults with locally advanced or metastatic unresectable solid tumors.
- INBRX-105 was administered intravenously every 2, 3, or 4 weeks, with dose escalation and expansion cohorts for both monotherapy and combination arms.
- Patients included those with checkpoint inhibitor-relapsed/refractory (CPI-R/R) or CPI-naïve disease, with safety and preliminary response as primary and secondary endpoints, respectively.
Main Results:
- The maximum tolerated dose of INBRX-105 was determined to be 0.3 mg/kg every 3 weeks.
- The most frequent treatment-related adverse events included fatigue, elevated aspartate aminotransferase, and nausea.
- Hepatotoxicity was a significant concern, with 41 patients experiencing INBRX-105-related hepatic adverse events.
- The overall objective response rate was 8.8% (monotherapy 3.7%, combination 13.9%), with a higher response rate of 30% in CPI-naïve patients receiving the combination therapy.
Conclusions:
- The observed low response rates and significant hepatic safety signals do not support the continued clinical development of INBRX-105.
- There is a continued need for novel immunotherapeutic combinations with non-redundant mechanisms to overcome tumor resistance and improve patient outcomes.
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