Search

TPS3162 Background: There are substantial data suggesting that a subset of human epidermal growth factor receptor 2 (HER2)–activating mutations induce ligand-independent constitutive HER2 signaling and promote oncogenesis. Direct therapeutic targeting of HER2 has transformed the treatment of patients with HER2-overexpressing breast and gastric cancers. However, currently no targeted treatments are approved for patients with tumors harboring HER2-activating mutations. T-DXd is an antibody-drug conjugate consisting of an anti-HER2 antibody, a cleavable tetrapeptide-based linker, and a membrane-permeable topoisomerase I inhibitor payload that may be selectively internalized in tumors with HER2 mutations (Li BT, et al. Cancer Discov. 2020;10:674-687). In a phase 1 study (DS8201-A-J101), T-DXd demonstrated preliminary antitumor activity in patients with tumors harboring HER2 mutations, with confirmed responses observed in 9 of 19 patients (47.4%) (Tsurutani J, et al. Cancer Discov. 2020;10:688-701). Here we describe the DESTINY-PanTumor01 trial (NCT04639219). Methods: DESTINY-PanTumor01 is an open-label, multicenter, single-arm, phase 2 study evaluating T-DXd for the treatment of patients with unresectable and/or metastatic solid tumors (excluding non-small cell lung cancer) harboring prespecified HER2-activating mutations. Patients (N≈100) are required to have progressed following prior treatment for advanced or metastatic disease or have no satisfactory alternative treatment options. Prior HER2-targeting therapy is allowed. HER2 mutation status will be determined locally using next-generation sequencing or a validated nucleic acid–based methodology. The primary endpoint is confirmed objective response rate according to independent central review per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Secondary endpoints include duration of response, disease control rate, progression-free survival, investigator-assessed confirmed objective response rate, overall survival, safety, pharmacokinetics, and immunogenicity. Clinical trial information: NCT04639219.

Therapeutic vaccination has the potential to contribute to functional HIV cure strategies. However, to show functional HIV cure, study participants must be taken off combination antiretroviral therapy (cART). The availability of suitable biomarkers that can predict viral load (VL) or CD4 count outcomes following therapeutic HIV vaccination would reduce the risks associated with cART interruption in such studies. This report sought to determine baseline and postvaccination biomarker predictors of vaccine effect (VE) on VL and CD4 counts following cART interruption in a double-blind, randomized phase 2 study of the peptide-based therapeutic HIV vaccine, Vacc-4x (n = 93), versus placebo (n = 43). Antibody responses to a novel envelope glycoprotein antigen, C5/gp41

Background In a randomized, double-blind, placebo-controlled phase 2 clinical trial of Vacc-4x, a peptide-based therapeutic HIV-1 p24 Gag vaccine candidate, 135 HIV-infected participants (vaccine:placebo = 92:43) received a series of six immunizations while on combination antiretroviral therapy (cART). At week 28, all participants underwent an analytical treatment interruption (ATI) for up to 24 weeks. preART VL appeared to be higher among Vacc-4x recipients. Based on a previous analysis, during ATI viral load (VL) appeared to be lower in Vacc-4x recipients, but no difference in CD4 level was observed between Vacc-4x and placebo groups. We propose fold-change-based endpoints and report comparative analyses accounting for imbalanced preART VL and missing data. Methods All analyses included per-protocol (PP) participants who received the full immunization and underwent ATI. Linear regression models were used to identify predictors of study endpoints and to estimate the vaccine effect based on fold changes in CD4 counts or VL over preART values at week 40 or at set-point (geometric mean over weeks 48 and 52 values). We adjusted for potential baseline factors and used a multiple imputation approach to account for missing endpoints due to cART resumption or dropout. P -values were adjusted for multiple comparisons using q -values. Results preART VL and CD4 count were significant predictors of study endpoints. The vaccine recipients had a higher fold change in week 40 CD4 counts (vaccine vs. placebo mean fold-change difference = 0.08; p = 0.02; q = 0.03), a higher fold change in CD4 count set-point (0.06; p = 0.06; q = 0.07), a lower fold change in week 40 VL (−0.47; p = 0.03; q = 0.05), and a lower fold change in VL set-point (−0.50; p = 0.02; q = 0.03). Conclusions These exploratory analyses consistently suggested that Vacc-4x provided positive effects on both CD4 counts and VL. Future HIV therapeutic vaccine studies may adopt similar preART-adjusted endpoints and missing data imputation methods in vaccine effect evaluations.

Background: Present combination antiretroviral therapy (cART) alone does not cure HIV infection and requires lifelong drug treatment. The potential role of HIV therapeutic vaccines as part of an HIV cure is under consideration. Our aim was to assess the efficacy, safety, and immunogenicity of Vacc-4x, a peptide-based HIV-1 therapeutic vaccine targeting conserved domains on p24Gag, in adults infected with HIV-1. Methods: Between July, 2008, and June, 2010, we did a multinational double-blind, randomised, phase 2 study comparing Vacc-4x with placebo. Participants were adults infected with HIV-1 who were aged 18-55 years and virologically suppressed on cART (viral load