Patient and Disease Characteristics
Seven CD30 positive and eleven CD30 negative patients with relapsed/refractory GCT (N=18) were enrolled between May 2016 and September 2018 at 3 academic institutions. One patient had unknown CD30 expression and was categorized and allocated to the CD30 negative group. Patient and disease characteristics are listed in Table 1. Median age was 35 (range 23-57 years). One female patient with ovarian GCT was enrolled (CD30 –ve). All patients had non-seminoma histology. Tumor markers where elevated in 16 out of 18 patients: AFP only in 5, hCG only in 10, both AFP and hCG in 1. Metastatic sites included retroperitoneal lymph nodes in 7 patients, pulmonary metastasis in 14 patients, liver metastasis in 8 patients, brain metastasis in one, and bone metastasis in 3. The median number of previous lines of chemotherapy was 3 (range 2-7). Ten patients (55.6%) had undergone prior high-dose chemotherapy and autologous stem-cell transplant. Twelve patients (66.7%) received prior ifosfamide or paclitaxel-containing salvage chemotherapy regimens. Five patients (27.8%) had late relapse defined as disease progression/recurrence more than 2 years after first line cisplatin-based combination chemotherapy.
Treatment Administration
All 18 patients enrolled in this study across both cohorts received at least one dose of brentuximab vedotin 1.8 mg/kg per study protocol. The median number of doses was 2 (range 2-4) in the CD30 positive cohort and 3 (range 1-6) in the CD30 negative cohort. One patient in the CD30 negative cohort received only 1 dose of brentuximab vedotin and died due to disease progression. Dose reductions were required for 2 CD30 negative patients due to adverse events.
Efficacy
No partial or complete responses were observed. Six out of 18 enrolled patients had stable disease. Five of the 6 patients with stable disease had elevated AFP or hCG at trial entry; all 5 patients had >50% decline in AFP or hCG which was transient and followed with rising markers at time of progression. Two of these 6 patients were in the CD30 positive cohort (stable disease for 9 and 11.7 weeks respectively), and 4 were in the CD30 –ve cohort (stable disease for 9, 9, 12, and 14.9 weeks respectively). Of the remaining 12 patients, 10 had progressive disease as their best response. One patient in the CD30 positive and 1 in the CD30 negative cohort were not evaluable for efficacy due to death from complications of disease prior to any disease evaluation. Tumor responses evaluated via RECIST 1.1 in CD30 –ve and CD30 positive cohorts are depicted in Figure 2. Note that the best response in 6 patients was determined solely based on rising tumor markers satisfying protocol criteria for disease progression. PFS and OS Kaplan–Meier curves are depicted in Figure 3 and 4 respectively (supplementary material, online only). Median PFS in the CD30 positive cohort was 1.2 months (95% CI: 0.9-2.1 months) and in the CD30 negative cohort was 1.4 months (95% CI: 0-2.1 months). Median OS in the CD30 positive cohort was 2.5 months (95% CI: 1.1-12.9 months) and in the CD30 negative cohort was 5.9 months (95% CI: 1.6-8.2 months).
Given no confirmed objective responses were observed among 10 response-evaluable patients in the CD30 negative cohort (one additional patient was unevaluable for response), the protocol-stipulated stopping criteria (<1/10 with response) were met and this cohort was closed for lack of efficacy rather than proceeding to the second Simon stage. The CD30 positive cohort was terminated before the interim analysis given slow accrual and lack of any signal of efficacy among the 6 response-evaluable patients. At last follow-up, 12 patients had died due to disease progression. There were no deaths due to toxicity.
Biomarker Analysis
Out of the 7 CD30 positive patients, 1 had cytoplasmic staining (3+ intensity), 5 had cell wall staining (three had 3+ intensity and two had 2+ intensity), and 1 had an unknown staining localization. The two patients with stable disease both had CD30 cell wall staining (2+ and 3+ respectively).
Toxicity
Brentuximab vedotin was generally tolerated in this patient population with 2 patients experiencing treatment-related grade 3 adverse events one with anemia and another with neutropenic fever. No grade 4 or 5 treatment-related adverse events were reported. Table 2 lists the most common adverse events reported.