Sorafenib monotherapy in patients with inoperable/recurrent germ cell tumors (GCT) refractory to chemotherapy: Phase II study.

Abstract

367 Background: The phase II trial was conducted in the population of incurable patients with refractory or relapsed GCT to evaluate the activity of sorafenib, an oral multitarget inhibitor of Raf kinase and the tyrosine kinases VEGFR-2 and PDGFR-alpha. Methods: Patients with progressive metastatic GCT received sorafenib monotherapy continuosly 400mg bid until progression of disease or unacceptable toxicity. Serum tumor markers (STM) were assessed every 4 weeks and imaging was performed every 12 weeks. Responses were assessed using RECIST; STM normalization was required for complete responses and partial responses required at least STM stabilization. STM-only declines were recorded as stable disease. Descriptive analysis of efficacy and tolerance was conducted. Results: 18 male patients with nonseminoma were included between 9/2008 and 6.2010. Pts received median 3 (range 3-4) prior chemotherapy treatments, 2 had received prior high-dose therapy. Median age was 35 (range 26-48), primary site was testicular in 16 and in 2 cases retroperitoneal. All patients had STM elevation before treatment. Median treatment duration was 83 days (31, 617), 12/18 patients were treated more than 2 cycles, 8 pts experienced some degree of STM decline with prolonged SD lasted more than 350 days in 3 pts. No partial or complete responses were observed. Drug related adverse events (AEs) were mainly grade 1 and 2; 55% of patients experienced diarrhea, 44% rash, 55% HFSR, 33% hypertension, 28% fatigue. Some G3 toxicity occurred: diarrhea in one pts, hypertension in one patient, HFSR in 2/18. 31% and 22% of pts required dose interruption and reduction respectively due to AEs. Conclusions: Sorafenib monotherapy was well tolerated but did not demonstrated significant activity in patients with highly refractory GCT, although there were some prolonged SD observed. Clinical trial information: NCT00772694.

Investigational targeted therapies for the treatment of testicular germ cell tumors

“…However, clinical results were rather disappointing, since sunitinib was the only agent to achieve short-lived partial remissions in 13% of 33 patients and was well tolerated in a phase II trial [20], but a second trial failed to confirm these results [21]. Pazopanib and sorafenib only induced tumor marker declines in 80% and 44% of patients in small phase II trials without any objective responses, but 33% of patients achieved progression-free survival of at least 3 months with pazopanib, and 17% of sorafenib-treated patients achieved disease stabilization for more than 12 months [22,23].…”

Will Testicular Germ Cell Tumors Remain Untargetable?

“…Brentuximab vedotin is an antibody-drug conjugate approved in Hodgkin lymphomas and systemic anaplastic large cell lymphoma targeting the CD30. This antigen is regularly expressed in embryonal carcinoma; when tested in salvage treatment of CD-30 positive germ cell tumors, the RR was 22.2 % with 6-month OS of 85.7 % [76]. Another phase II associating bevacizumab combined with high-dose chemotherapy with autologous stem-cell transplant demonstrated an OS of 58.1 % with a follow-up of 46 months [77].…”

“…At the ASCO annual meeting 2014, two abstracts were presented evaluating antiangiogenic TKI, pazopanib and sorafenib in chemo-resistant, heavily treated germ cell tumors. Pazopanib is endowed with preliminary activity [75], while Sorafenib did not present significant activity in patients despite some prolonged stable diseases [76]. Another abstract in ASCO 2014 evaluated Alvocidib/Flavopiridol, a CDK9 inhibitor, in combination with oxaliplatin with or without fluorouracil and leucovorin calcium in a phase II trial that showed an RR of 24 % in Alvocidib/FOLFOX arm and a PFS of 2.3 months and a OS of 7.3 months [74].…”

Immune Checkpoint Inhibitors in Genitourinary Malignancies

“…However, those treatments fail about 15%-20% of patients, a subgroup that is thus in need of additional treatment options. Recent trials using targeted therapies in such patients have yielded disappointing results [38][39][40][41] . Although gcts have been shown to express PD-L1 42 , and a number of case studies and series have described activity for cpis in those tumours [43][44][45] , early-phase trials have been disappointing to date.…”