KEY TAKEAWAYS
- The n phase 2 study aimed to investigate the selective depletion of CD30-expressing activated Tregs by BV in combination with pembrolizumab.
- The primary endpoint was to determine ORR.
- Researchers observed BV’s potential to re-sensitize anti-PD-1 resistant tumors through selective CD30-directed Treg depletion; further information will be provided later.
Patients (pts) with primary or secondary refractory non-small cell lung cancer (NSCLC) or melanoma, post anti-PD-1 therapy, received brentuximab vedotin (BV) and pembrolizumab (pembro) in a 21-day cycle. The study explores BV’s potential to re-sensitize tumors through CD30-directed Treg depletion. Preliminary findings show promising response rates, encouraging further investigation for relapsed/refractory melanoma and NSCLC in the ongoing SGN35–033 trial.
Sylvia Lee and her team aimed to explore BV+pembro in frontline NSCLC and head and neck cancer in the ongoing SGN35–033 trial. The objective was to assess the efficacy and safety of BV+pembro in refractory NSCLC and melanoma, exploring biomarkers and observing increased CD8 T cells in responders.
The study performed an inclusive analysis involving pts with primary or secondary refractory NSCLC or melanoma who experienced progression on anti-PD-1 therapy. Subjects underwent 21-day cycles of BV at 1.8 mg/kg and pembrolizumab at 200 mg. The primary endpoint centered on the confirmed objective response rate (ORR), evaluated by investigators using RECIST v1.1 criteria. Exploratory biomarker assessments included T cell subsets through peripheral blood flow cytometry, immunohistochemistry (IHC) for CD8 and Foxp3, and RNA sequencing of tumor biopsies collected at baseline and on cycle 3 day 1.
The study performed an inclusive analysis involving pts with primary or secondary refractory NSCLC or melanoma who experienced progression on anti-PD-1 therapy. Subjects underwent 21-day cycles of BV at 1.8 mg/kg and pembrolizumab at 200 mg. The primary endpoint centered on the confirmed objective response rate (ORR), evaluated by investigators using RECIST v1.1 criteria. Exploratory biomarker assessments included T cell subsets through peripheral blood flow cytometry, immunohistochemistry (IHC) for CD8 and Foxp3, and RNA sequencing of tumor biopsies collected at baseline and on cycle 3 day 1.
About 54 patients with NSCLC and 58 patients with melanoma, all refractory to anti-PD-1 therapy, were enrolled, including 11 primary and 43 secondary refractory NSCLC cases, and 17 primary and 41 secondary refractory melanoma cases. These heavily pretreated individuals had a median of 3 prior lines of therapy (range: 1–10). The overall response rate (ORR) reached 20% across cohorts, with a disease control rate (DCR) ranging from 64% to 80%.
Notably, an exploratory analysis indicated numerically higher response rates in patients with tumors exhibiting elevated PD-L1 expression. No new safety signals were observed. Preliminary IHC and RNA sequencing analyses of tumor biopsies from responders revealed increased tumor-infiltrating CD8 T cells at cycle 3 day 1 post-treatment. Transcriptome-wide RNA expression analyzes in responders showcased enrichment of genes associated with T cell signaling, Treg biology, and antigen presentation in baseline tumor biopsies, aligning with the hypothesized immune modulatory effects of BV.
The study concluded that BV exhibits potential in re-sensitizing anti-PD-1 resistant/refractory tumors to PD1 through targeted CD30-directed depletion of regulatory T cells (Tregs). Treatment with BV in combination with pembrolizumab was associated with the selective depletion of CD30+ Tregs and modulation of the tumor microenvironment, alleviating Treg immunosuppression.
These findings provide support for further exploration of the brentuximab vedotin+pembro combination in the treatment of relapsed/refractory melanoma and NSCLC. Ongoing enrollment of cohorts in the SGN35–033 trial aims to investigate the activity of BV+pembro in frontline NSCLC and head and neck cancer.
The study is sponsored by Seagen Inc.
Source: https://jitc.bmj.com/content/11/Suppl_1/A794
Clinical Trial: https://clinicaltrials.gov/study/NCT04609566
Lee S, Jotte R M, Twardy A G, et al. (2023).” Phase 2 trial of brentuximab vedotin (BV) with pembrolizumab (pembro) in patients with metastatic non-small cell lung cancer or metastatic cutaneous melanoma after progression on anti-PD-1 therapy.” Presented at SITC 2023 (Abstract 699).
