Improved efficacy of pembrolizumab combined with soluble EphB4-albumin in HPV-negative EphrinB2 positive head neck squamous cell carcinoma.

OBJECTIVE: Patients with relapsed or metastatic head and neck squamous cell carcinoma (HNSCC) after primary local therapy have low response rates with cetuximab, systemic chemotherapy or check point inhibitor therapy. Novel combination therapies with the potential to improve outcomes for patients with HNSCC is an area of high unmet need. METHODS: This is a phase II single-arm clinical trial of locally advanced or metastatic HNSCC patients treated with a combination of soluble EphB4-human serum albumin (sEphB4-HSA) fusion protein and pembrolizumab after platinum-based chemotherapy with up to 2 prior lines of treatment. The primary endpoints were safety and tolerability and the primary efficacy endpoint was overall response rate (ORR). Secondary endpoints included progression free survival (PFS) and overall survival (OS). HPV status and EphrinB2 expression were evaluated for outcome. RESULTS: Twenty-five patients were enrolled. Median follow up was 40.4 months (range 9.8 - 40.4). There were 6 responders (ORR 24%). There were 5 responders in the 11 HPV-negative and EphrinB2 positive patients, (ORR 45%) with 2 of these patients achieving a complete response (CR). The median PFS in HPV-negative/EphrinB2 positive patients was 3.2 months (95% CI 1.1, 7.3). Median OS in HPV-negative/EphrinB2 positive patients was 10.9 months (95% CI 2.0, 13.7). Hypertension, transaminitis and fatigue were the most common toxicities. DISCUSSION: The combination of sEphB4-HSA and pembrolizumab has a favorable toxicity profile and favorable activity particularly among HPV-negative EphrinB2 positive patients with HNSCC.

EphrinB2: Expression of a novel potential target in renal cell carcinoma.

Introduction: Renal cell carcinoma (RCC) is primarily managed by surgery with the use of systemic targeted therapy in a metastatic setting. Newer targeted therapeutic options are evolving; Eph-ephrin is a potential new pathway. The therapeutic potential of targeting the EphB4-EphrinB2 pathway has been demonstrated in many solid tumors; however, its expression in RCC has only been evaluated in a few studies with limited cases. We herein determine the immunohistochemical expression of EphrinB2 in RCC. Methods: A tissue microarray comprising 110 cases of different histological subtypes of RCC and 10 normal kidney tissues were stained with monoclonal anti-EphrinB2 antibody (Abcam, AB201512). The tumor and endothelial cells expressing the EphrinB2 were examined and its expression was correlated with sex, histological subtypes, and tumor nodes metastasis (TNM) stage. Results: Twenty cases of urothelial carcinoma and two unsatisfactory conventional clear cell RCC cases were excluded, and EphrinB2 expression was interpreted in the remaining 88 tumors. EphrinB2 was expressed in 42 out of 88 tumors (47.7%) and was negative in the normal renal parenchyma. There was a statistically significant difference in the expression of EphrinB2 in males (55%) and females (32%). However, no such difference of expression was noted for the histological subtypes and the stages. Half (51%) of Stage 1 (n = 30) and Stage 2 (n = 11) tumors showed EphrinB2 positivity. Conclusions: EphrinB2 is expressed in approximately half of RCC cases. EphrinB2 expression in the early stage cancer might indicate its induction as an early event.

EphrinB2 Inhibition and Pembrolizumab in Metastatic Urothelial Carcinoma.

PURPOSE: Patients with metastatic urothelial carcinoma have poor prognosis after failure of standard first-line chemotherapy. Immune check point programmed death 1-programmed death ligand 1 antibodies have low response rates and thus there exists a major unmet need. MATERIALS AND METHODS: In this phase II trial, patients with metastatic urothelial carcinoma that recurred or progressed after platinum-based chemotherapy received soluble EphB4-human serum albumin (sEphB4-HSA) in combination with pembrolizumab. The primary end points were tolerability and overall survival (OS). The secondary end points were progression-free survival (PFS), objective response rate (ORR), duration of response, and toxicity. The expression of sEphB4-HSA target EphrinB2 was correlated with outcomes. RESULTS: Seventy patients were enrolled. The median follow up was 22.9 months (range, 1.3-54.7). The regimen had acceptable toxicity. In the intent-to-treat analysis (N = 70), the median OS was 14.6 months (95% CI, 9.2 to 21.5). Twenty-six (37%) patients had an objective response (95% CI, 26 to 48). The median PFS was 4.1 (95% CI, 1.5 to 5.7) months. Forty-six (66%) patients expressed EphrinB2, and among them, the median OS was 21.5 months (95% CI, 12.4 to not reached), the ORR was 52% (95% CI, 37 to 67), including a complete response rate of 24% (11 of 46; 95% CI, 12 to 36). The median PFS was 5.7 (95% CI, 2.7 to 27.9) months. Response was maintained at 6, 12, and 24 months in 88%, 74%, and 69% of the patients, respectively. CONCLUSION: The combination of sEphB4-HSA and pembrolizumab appears synergistic with improved OS and ORR compared with historical data for programmed death 1/programmed death ligand 1 monotherapy.

EphrinB2 expression in prostate adenocarcinoma: Implications for targeted therapy.

BACKGROUND: Prostate cancer is managed by surgery, androgen deprivation and cytotoxic chemotherapy. Targeted therapy is emerging as an important pillar in cancer therapeutics, however, efficacy in prostate cancer has been limited. Eph-ephrin is a novel pathway that is upregulated in prostate cancer and promotes the initiation and progression of cancer. The aim of this study was to determine the immunohistochemical expression of ephrinB2 in prostate adenocarcinoma. METHODS: A tissue microarray comprising of prostate adenocarcinoma of different grade groups was stained with a monoclonal anti-ephrinB2 antibody (Abcam, AB201512). The tumor and endothelial cells expressing the ephrinB2 positivity were noted. The statistical analysis was performed to determine the difference in expression based on grade groups and the TNM stage. RESULTS: EphrinB2 was expressed in 40 out of 72 cases (55.5 %) of prostate adenocarcinoma and was predominantly negative in the normal prostatic tissue. There was no significant difference in the expression of ephrinB2 in various grade groups (p = 0.7) or stages (p = 0.6). CONCLUSIONS: EphrinB2 is expressed in a significant number of prostate adenocarcinoma regardless of grade and stage. Hence, there is a potential to target this molecule in the low-grade tumors with localized disease as well as high grade, high volume tumors with metastatic disease.