Phase II trial of nivolumab monotherapy and biomarker screening in patients with chemo‐refractory germ cell tumors

Abstract

Objectives: Germ cell tumors are highly susceptible to chemotherapy; however, there is a lack of established treatments for consistently relapsing germ cell tumor. Therefore, in this phase II study, we evaluated the efficacy and safety of nivolumab for relapsed germ cell tumor. Methods: Seventeen adult patients (median age 34 years) with refractory primary germ cell tumor after second-line or higher chemotherapy were enrolled. Nivolumab was administered over 30 min at 240 mg/body every 2 weeks until disease progression or intolerable adverse event occurrence. The primary endpoint was the overall response rate.Result: We performed a biomarker analysis of programmed death ligand-1 expression and genomic sequencing. Tumor histology revealed nonseminoma and seminoma in 14 and three patients, respectively. Patients were pretreated with a median of three chemotherapy lines, and three patients received high-dose chemotherapy. The median number of nivolumab doses was 3 (range 2-46). One patient showed a partial response and three showed stable disease. Responses were durable in one patient with a partial response and one patient with stable disease (median 90 and 68 weeks, respectively). Nivolumab was well-tolerated, with only two Grade 3 adverse events observed. Programmed death ligand-1 expression was not associated with objective responses. Genomic sequencing revealed a high tumor mutation burden in a patient with a durable partial response. While a small subset of chemorefractory germ cell tumors may respond to nivolumab, programmed death ligand-1 is unreliable to measure response. Conclusions: Tumor mutation burden is a potential biomarker for future testing of germ cell tumor response.

Editorial Comment to Plasma circulating tumor DNA profiling in patients with chemo‐refractory germ cell tumors

“…For these chemo‐refractory patients, the results of a phase II trial using nivolumab were recently reported. In this small trial ( n = 17), one patient (5.8%) had a partial response (PR) and three (17.6%) had stable disease (SD) and, notably, the maximum response duration of patients with PR and SD was 90.1 and 68.4 weeks, respectively 3 . Although the proportion of patients who benefitted from nivolumab was low, this phase II study suggested that nivolumab is worth considering if predictive biomarkers are available 3 …”

“…In this small trial (n = 17), one patient (5.8%) had a partial response (PR) and three (17.6%) had stable disease (SD) and, notably, the maximum response duration of patients with PR and SD was 90.1 and 68.4 weeks, respectively. 3 Although the proportion of patients who benefitted from nivolumab was low, this phase II study suggested that nivolumab is worth considering if predictive biomarkers are available. 3 In this issue of the International Journal of Urology, Sakka et al investigated plasma circulating tumor DNA profiling in 13 patients with chemo-refractory germ cell tumors who participated in the phase II nivolumab study.…”

“…3 Although the proportion of patients who benefitted from nivolumab was low, this phase II study suggested that nivolumab is worth considering if predictive biomarkers are available. 3 In this issue of the International Journal of Urology, Sakka et al investigated plasma circulating tumor DNA profiling in 13 patients with chemo-refractory germ cell tumors who participated in the phase II nivolumab study. 3,4 Tumorspecific genetic alterations were identified in all patients.…”

“…3 In this issue of the International Journal of Urology, Sakka et al investigated plasma circulating tumor DNA profiling in 13 patients with chemo-refractory germ cell tumors who participated in the phase II nivolumab study. 3,4 Tumorspecific genetic alterations were identified in all patients. 4 The most frequently mutated gene was TP53 (53.4%), followed by PTEN (23.1%), GNAS (15.4%), and MTOR (15.4%).…”

Editorial Comment to Phase II trial of nivolumab monotherapy and biomarker screening in patients with chemo‐refractory germ cell tumors

“…In the article by Kawahara et al , the authors present data from a phase II trial investigating the safety and efficacy of nivolumab in a cohort of 17 adults with refractory germ cell tumors aligned with an analysis of programmed death ligand‐1 (PD‐L1) expression and genomic sequencing 4 . The overall clinical activity of nivolumab was sobering, but one patient revealed a durable partial response, associated with the proof of a high tumor mutational burden.…”