Neoplasms Clinical Trial
Official title:
Phase II Study of Avelumab in Multiple Relapsed/Refractory Testicular Germ Cell Cancer.
This is a proof-of-concept study to define efficacy of AVELUMAB in patients with multiple relapsed/refractory germ cell tumors (GCTs). Data suggest that PD-L1 is overexpressed in TGCTs, and PD-L1 expression is significantly higher in GCTs in comparison to normal testicular tissue.Patients with low PD-L1 expression had significantly better progression-free survival (hazard ratio [HR] = 0.40, 95% CI (0.16 - 1.01, p = 0.008) and overall survival (HR = 0.43, 95% CI (0.15 - 1.23, p = 0.040) compared to patients with high PD-L1 expression. These data suggest that PD-1/PD-L1 pathway could be a novel therapeutic target in TGCTs and that there is strong rationale to inhibit PD-1/PD-L1 signaling in GCTs.
Germ-cell tumours (GCTs) are extraordinarily chemosensitive and resemble the clinical and
biological characteristics of a model for the cure of cancer. Nonetheless, a small proportion
of patients do not have a durable complete remission (CR) with initial chemotherapy. Only
20-40% of them will be cured with the use of platinum-containing standard-dose or high-dose
salvage chemotherapy with autologous stem cell transplantation (ASCT). Patients who fail to
be cured after second-line salvage therapy have an extremely poor prognosis and long term
survival had been documented in <5%. Paclitaxel plus ifosfamide and cisplatin is considered
as a standard salvage chemotherapy in relapsed good prognosis GCTs, however, up to 40% of
favourable prognosis patients failed to achieve durable response to this combination, and
therefore new treatment strategies are warranted.
Recent data suggest that PD-L1 is overexpressed in TGCTs, including 73% seminomas and 64%
non-seminomatous tumors, but none of normal testicular tissue specimens exhibited PD-L1
expression. In previous study that included 140 patients, PD-L1 was significantly higher in
GCTs in comparison to normal testicular tissue (mean QS = 5.29 vs. 0.32, p < 0.0001).
Choriocarcinomas exhibit the highest level of PD-L1 with decreasing positivity in embryonal
carcinoma, teratoma, yolk sac tumor and seminoma. PD-L1 expression was associated with poor
prognostic features including ≥ 3 metastatic sites, increased serum tumor markers and/or
non-pulmonary visceral metastases. Patients with low PD-L1 expression had significantly
better progression-free survival (hazard ratio [HR] = 0.40, 95% CI (0.16 - 1.01, p = 0.008)
and overall survival (HR = 0.43, 95% CI (0.15 - 1.23, p = 0.040) compared to patients with
high PD-L1 expression (Figure 1).
These data suggest that PD-1/PD-L1 pathway could be a novel therapeutic target in TGCTs and
that there is strong rationale to inhibit PD-1/PD-L1 signaling in GCTs and phase II study is
warranted.
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