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VEGF inhibition in gastric cancer has a proven benefit in the second line setting. Pazopanib, an oral tyrosine kinase inhibitor, selectively inhibits VEGFR-1, -2 and -3, c-kit and PDGF-R resulting in inhibition of angiogenesis. This open-label randomized phase II trial (2:1) investigated the efficacy of combining pazopanib with FLO (5-fluorouracil, oxaliplatin) vs FLO alone (internal control arm) as first-line treatment in patients with advanced adenocarcinoma of the stomach and gastroesophageal junction (GEJ). Eighty-seven patients were randomized and 78 patients were eligible and evaluable (PaFLO arm 51 patients, FLO arm 27 patients). The PFS rate at 6 months (primary endpoint) was 34% in the PaFLO arm vs 30% in the FLO arm. Comparing PaFLO with FLO median PFS was 4.66 months (95% confidence interval [CI] 2.87-6.46) vs 4.47 months (95% CI 1.79-7.14) (95% CI, hazard ratio [HR] 0.96 (0.60-1.55), P =.882 [exploratory]); median OS was 10.19 months (95% CI 5.46-14.92) vs 7.33 months (95% CI 4.93-9.73), (95% CI HR 1.01 [0.62-1.65], P =.953, exploratory), disease control rate was 72% vs 59%. PaFLO was well tolerable, toxicities were slightly higher in the PaFLO arm. Major adverse events were loss of appetite, nausea, fatigue, diarrhea, neutropenia and thrombocytopenia. Adding pazopanib to chemotherapy shows signs of efficacy but no major improvement in this randomized phase 2 trial. The PFS at 6 months in both arms was lower than expected from the literature. Biomarkers identifying subgroups who benefit and novel combinations are needed. ClinicalTrials.gov: NCT01503372.

Immune checkpoint inhibitors enrich the therapeutic landscape in oesophago-gastric carcinoma. With regard to oesophageal squamous cell carcinoma (ESCC), the selective PD-1 (programmed cell death receptor 1)-inhibitor nivolumab improves disease-free survival in the adjuvant therapy setting (CHECKMATE-577). In first-line treatment, ESCC patients (pts) benefit in overall survival (OS) from the PD-1-inhibitor pembrolizumab in combination with chemotherapy (KEYNOTE-590). In the second-line setting, nivolumab (ATTRACTION-03) and pembrolizumab (KEYNOTE-181) demonstrate a benefit in OS compared with chemotherapy. These data resulted in the approval of nivolumab for the second-line treatment of advanced ESCC pts regardless of PD-L1 (programmed cell death ligand 1) status in Europe, Asia, and the USA, and pembrolizumab for pts with PD-L1 CPS (combined positivity score) ≥ 10 in Asia and the USA. Further approvals can be expected. In gastro-oesophageal junction and gastric cancer, the addition of nivolumab to chemotherapy in first-line treatment improves OS in pts with advanced disease with PD-L1 CPS ≥ 5 (CHECKMATE-649). Additionally, pembrolizumab was non-inferior to chemotherapy for OS in PD-L1 CPS ≥ 1 pts (KEYNOTE-062). In third-line treatment, nivolumab shows benefits in OS regardless of PD-L1 expression (ATTRACTION-02) with approval in Asia, and pembrolizumab prolonged the duration of response in PD-L1 positive pts (KEYNOTE-059) with approval in the USA. We discuss the recent results of the completed phase II and III clinical trials.

VEGF inhibition in gastric cancer has a proven benefit in the second line setting. Pazopanib, an oral tyrosine kinase inhibitor, selectively inhibits VEGFR-1, -2 and -3, c-kit and PDGF-R resulting in inhibition of angiogenesis. This open-label randomized phase II trial (2:1) investigated the efficacy of combining pazopanib with FLO (5-fluorouracil, oxaliplatin) vs FLO alone (internal control arm) as first-line treatment in patients with advanced adenocarcinoma of the stomach and gastroesophageal junction (GEJ). Eighty-seven patients were randomized and 78 patients were eligible and evaluable (PaFLO arm 51 patients, FLO arm 27 patients). The PFS rate at 6 months (primary endpoint) was 34% in the PaFLO arm vs 30% in the FLO arm. Comparing PaFLO with FLO median PFS was 4.66 months (95% confidence interval [CI] 2.87-6.46) vs 4.47 months (95% CI 1.79-7.14) (95% CI, hazard ratio [HR] 0.96 (0.60-1.55), P = .882 [exploratory]); median OS was 10.19 months (95% CI 5.46-14.92) vs 7.33 months (95% CI 4.93-9.73), (95% CI HR 1.01 [0.62-1.65], P = .953, exploratory), disease control rate was 72% vs 59%. PaFLO was well tolerable, toxicities were slightly higher in the PaFLO arm. Major adverse events were loss of appetite, nausea, fatigue, diarrhea, neutropenia and thrombocytopenia. Adding pazopanib to chemotherapy shows signs of efficacy but no major improvement in this randomized phase 2 trial. The PFS at 6 months in both arms was lower than expected from the literature. Biomarkers identifying subgroups who benefit and novel combinations are needed. ClinicalTrials.gov: NCT01503372.

Hintergrund Im klarzelligen Nierenzellkarzinom (NZK) weist PBRM1 (Polybromo-1 Gen) ca. 40% somatische Genmutationen auf und wurde neben VHL (von Hippel-Lindau Gen) als zweithäufigstes mutiertes Two-hit-Tumorsuppressorgen identifiziert. Obwohl die sporadische Inaktivierung von VHL im klarzelligen NZK mit ca. 90% überwiegt, könnte PBRM1 eine Schlüsselrolle in den Fällen einnehmen, in denen ein VHL-Verlust allein nicht für die Entstehung eines NZK ausreicht. Das Ziel unserer Studie war es, den Einfluss der PBRM1- und VHL–Expression auf dem mRNA- und Protein-Level auf die klinisch-pathologischen Eigenschaften der Tumoren und das Überleben der Patienten mit klarzelligem NZK zu identifizieren. Methoden An dem Kryomaterial von Tumor- und entsprechendem Normalgewebe von 70 nephrektomierten Patienten wurden für PBRM1 und VHL immunhistologische Färbungen, Western Blots und quantitative PCR-Analysen durchgeführt. Zusätzlich wurde ein großes Patientenkollektiv mit 326 klarzelligen NZK-Patienten eines Tissue Micro Array (TMA) dazu verwendet, den Effekt des PBRM1- und VHL-Expressionsverlustes im Gewebeschnitt auf die klinisch-pathologischen Faktoren der Tumoren und das Gesamt-Überleben der Patienten zu untersuchen. Ergebnisse In beiden Patientenkollektiven (Kryomaterial, TMA) waren Männer insgesamt häufiger vom klarzelligen NZK betroffen als Frauen (68.1%, bzw. 64.4%). Dabei wies der Großteil der Patienten der Gruppe mit dem Kryomaterial größere Tumoren auf (pT 3/4, n = 38/70), während in der TMA-Gruppe der Großteil der Patienten kleinere Tumoren aufzeigte (pT1/2, n = 212/326). In der Mehrheit der Patienten der Gruppe mit dem gefrorenen Tumorgewebe waren die PBRM1- und VHL–mRNA signifikant herunterreguliert (77.6% / 80.6%). In dieser Gruppe zeigten 21.4% der Tumoren in der Immunhistologie eine simultan schwache PBRM1- und VHL-Proteinexpression auf. Hingegen konnten wir in 60.4% der TMA-Tumoren eine schwache PBRM1- und VHL-Proteinexpression nachweisen, die signifikant miteinander korrelierte (P < 0.001). Der Einfluss der immunhistologischen PBRM1- und VHL–Expression auf die klinisch-pathologischen Parameter zeigte ein variables Bild: so war eine schwache PBRM1- und VHL–Expression zwar signifikant mit einem höheren Fuhrman-Grade assoziiert (P = 0.012 und 0.024), jedoch wies nur eine schwache VHL Expression eine Assoziation zu größeren Tumoren auf (pT 3/4, P = 0.023). Eine schwache immunhistologische VHL-Expression war mit einem kürzeren Gesamtüberleben der Patienten assoziiert (P = 0.013), während PBRM1 keinen Einfluss auf das Überleben der Patienten zeigte. Schlussfolgerung Die Ergebnisse unserer Studie deuten darauf hin, dass eine reduzierte Expression von PBRM1 und VHL mit einer erhöhten Tumoraggressivität korreliert ist. Wir konnten eine nur noch geringe VHL-Expression als unabhängigen Risikofaktor für das kürzere Gesamtüberleben von Patienten mit klarzelligem NZK identifizieren., Background In clear cell renal cell carcinoma (ccRCC), PBRM1 (Polybromo-1 gene) harbors about 40% truncating somatic mutations and was identified as the second most frequently mutated two-hit tumor suppressor gene, next to VHL (von Hippel-Lindau gene). Although sporadic inactivation of VHL is predominant in ccRCC (~ 90%), PBRM1 may have a putative gatekeeper function in cases where VHL loss alone is insufficient for ccRCC tumorigenesis. The aim of this study was to identify the impact of PBRM1 and VHL expression at mRNA and protein levels on clinicopathological features and patient outcome in ccRCC. Methods In fresh frozen tumor and adjacent normal tissue from 70 patients who underwent radical nephrectomy, immunohistochemical stainings, Western blotting and qPCR analysis of PBRM1 and VHL were performed. In addition, a tissue micro array (TMA) consisting of 326 ccRCC patient samples was used to identify the effect of loss of PBRM1 and VHL immunohistological expression on clinicopathological factors and patient overall survival. Results In both groups of fresh frozen ccRCC and TMA samples, men were more affected by ccRCC compared to women (68.1% / 64.4%). Large tumors of pT3/4 stage prevailed in fresh frozen samples (pT3/4, n = 38/70), whereas small tumors predominated in TMA samples (pT1/2, n = 212/326). In the majority of ccRCC fresh frozen tumor samples, both PBRM1 and VHL mRNA were significantly down-regulated (77.6% / 80.6%). In this group, 21.4% of frozen tumors showed simultaneous weak PBRM1 and VHL protein expression in immunohistochemistry. However, 60.4% of the TMA samples showed weak PBRM1 and VHL immunohistochemical expression which was correlated significantly (P < 0.001). In view of the impact of PBRM1 and VHL expression in immunohistochemistry on clinicopathological features, weak PBRM1 and VHL expression was associated with higher Fuhrman grade, significantly (P = 0.012 and 0.024, respectively). Interestingly, only weak VHL expression was associated with larger tumors (pT 3/4, P = 0.023). Accordingly, there was an association of weak VHL immunohistological expression with decreased patient overall survival (P = 0.013), while PBRM1 expression did not affect the patient’s overall survival. Conclusions Our results indicate a correlation of reduced expression of PBRM1 and VHL with an increased tumor aggressiveness. We identified low VHL expression as an independent risk factor for worse patient outcome.