A phase II trial of cabozantinib in relapsed refractory germ-cell tumors (GCT).

587 Background: Vascular endothelial growth factor overexpression, increased angiogenesis, and activation of the c-MET pathway have biologic importance in GCT. Cabozantinib is an oral tyrosine-kinase inhibitor targeting c-MET, VEGF, RET, and AXL. We report results from a phase II trial of cabozantinib in refractory GCT. Methods: This single arm phase II trial used a Simon two-stage design investigating cabozantinib 60mg in pts with incurable relapsed/refractory GCT. Pts age≥18 with progressive metastatic GCT after first line cisplatin-based chemo and at least 1 salvage regimen were eligible. Primary endpoint was clinical benefit rate (CBR) proportion of complete response (CR), partial response (PR), and stable disease (SD) for ≥3 mos using RECIST 1.1, modified to include AFP and hCG. Simon’s 2-stage required clinical benefit in ≥ 2/18 pts to proceed to stage 2 and then enrolled up to 50 pts. Results: Simon stage I was met and expanded to stage 2. 44 pts were evaluable. 2 pts were female. Median age was 34.2 (21.4-63.2). 42 pts (95.5%) had nonseminomatous GCT. Primary site was testis for 79.5%, mediastinal 13.6%, ovary 4.6%, and retroperitoneal 2.3%. IGCCCG risk at initial diagnosis was good for 22.7%, intermediate 25%, poor 47.8%, and unknown 4.5%. 18 pts had late relapse disease. Median prior chemo regimens was 4. 63.6% of pts previously received high-dose chemotherapy with peripheral blood stem-cell transplant. Median AFP was 210.3 (1.1-120,693); hCG was 0.95 (0.6-72,759). CBR was 43.2%, with 2 pts (4.5%) achieving a PR and 17 (38.6%) achieving SD for ≥3 months. No CRs were seen. Median duration of treatment was 74 days (27-848). For those with SD as best response, median duration of SD was 3.7 mos (2.0-18.5). Stable radiographic disease was seen in 50% of pts, with median duration of 4.1 mos (2.01-27.9). Any measurable disease decrease was seen in 18 pts (46.2%). 95.5% of pts had AFP or hCG reduction, with 65.9% achieving at least 50% AFP or hCG reduction and 27.3% achieving at least 80% AFP or hCG reduction. The most common adverse event (AE) was diarrhea, occurring in 59.1% of pts, with 96.2% being G1/G2. Most common grade ≥3 AE was increased AST, occurring in 6.8% of pts. Table 1 lists AEs occurring in >25% of pts. 11 pts required dose reduction. 2 remain on treatment. Conclusions: Cabozantinib is the first non-cytotoxic chemotherapeutic agent with clinical benefit in refractory GCT. While no CRs were seen, clinical benefit was achieved in > 40% of pts, with half with stable radiographic response for a median of 4.1 mos. The AE profile has little overlapping toxicities with cytotoxic GCT chemo, presenting a unique opportunity to have less cumulative toxicity of further platinum chemo. Clinical trial information: NCT03375320 . AEs occurring in >25% of pts. Any Grade (%) Grade ≥3 (%) Diarrhea 26 (59.1) 1 (2.3) AST increased 24 (54.5) 3 (6.8) ALT increased 24 (54.5) 1 (2.3) Hypothyroid 22 (50) - Fatigue 20 (45.5) - Palmar-plantar erythrodysesthesia syndrome 19 (43.2) - Oral mucositis 13 (29.6) -