Effect of AdAPT-001 on checkpoint inhibitor resistance in solid tumors.

Abstract

2618 Background: Checkpoint inhibitors (CIs) have revolutionized cancer treatment, but most patients do not respond to them because of primary or secondary resistance. Introduction or reintroduction of CIs to resistant patients is relatively contraindicated because of the likelihood of an unfavorable harm-benefit profile. An intensive search is on for therapies that sensitize resistant tumors to CI therapy. AdAPT-001 is an oncolytic adenovirus armed with a transforming growth factor beta (TGFβ) trap that eliminates the immunosuppressive cytokine, TGFβ. Clinical data demonstrate that AdAPT-001 reverses the tumor immune evasion phenotype and improves the efficacy of immune checkpoint therapy, increasing response rate and progression-free survival (PFS) in CI refractory angiosarcoma. Methods: Patients with CI-refractory solid cancers of any type including sarcomas, melanoma, and breast cancer who received AdAPT-001 with a concurrent checkpoint inhibitor. Response was assessed every 8 weeks using RECIST 1.1. Treatment beyond progression was allowed for patients clinically benefiting, and if progression was confirmed on the next assessment then the first assessment meeting PD criteria was considered the date of progression. PFS on AdAPT-001 + CI was compared to duration of treatment on the most recent previous regimen including a CI before study enrollment. Results: Among all patients who were treated with a CI in a previous line of therapy (Prior CI) before being treated with AdAPT-001 + CI, the 6-month PFS rate was 17% (3/18) with Prior CI and 33% (6/18) with AdAPT-001 + CI, and the 12-month PFS rate was 0% (0/18) with Prior CI and 17% (3/18) with AdAPT-001 + CI. Particular activity was seen in angiosarcoma, where all patients progressed within 3 months on Prior CI and 75% (3/4) had PFS > 11 months with AdAPT-001 + CI. Treatment with AdAPT-001 was well tolerated and no new safety signals emerged. Conclusions: CI treatment is not an option for many patients because of primary or secondary resistance to them and the potential for harm without benefit. The data from this P2 clinical trial strongly suggests that AdAPT-001 circumvents resistance to CIs in multiple tumor types, improving PFS when compared to the patient’s prior CI regimen. In addition, AdAPT-001 may prevent the development of CI-induced autoimmune toxicities. P3 clinical trials in sarcoma and hepatocellular carcinoma are planned. Clinical trial information: NCT04673942 . Duration of treatment on a previous CI regimen compared to subsequent PFS with AdAPT-001 + CI. Subject ID Months on prior CI regimen PFS (months) with AdAPT-001 + CI PFS Change (months) 1 3.0 11.4 +8.4 2 3.0 2.0 -1.0 3 1.9 13.0 +11.1 4 2.7 12.0 +9.3 Median 2.8 11.7 +8.9