First-in-human phase 1 study of the anti-TIGIT antibody vibostolimab as monotherapy or with pembrolizumab for advanced solid tumors, including non-small-cell lung cancer☆.

BACKGROUND: In this first-in-human phase 1 study (NCT02964013; MK-7684-001), we investigated the safety and efficacy of the anti-TIGIT (T cell immunoglobulin and ITIM domain) antibody vibostolimab as monotherapy or in combination with pembrolizumab. PATIENTS AND METHODS: Part A enrolled patients with advanced solid tumors, and part B enrolled patients with non-small-cell lung cancer (NSCLC). Patients received vibostolimab 2.1-700 mg alone or with pembrolizumab 200 mg in part A and vibostolimab 200 mg alone or with pembrolizumab 200 mg in part B. Primary endpoints were safety and tolerability. Secondary endpoints included pharmacokinetics and objective response rate (ORR) per RECIST v1.1. RESULTS: Part A enrolled 76 patients (monotherapy, 34; combination therapy, 42). No dose-limiting toxicities were reported. Across doses, 56% of patients receiving monotherapy and 62% receiving combination therapy had treatment-related adverse events (TRAEs); grade 3-4 TRAEs occurred in 9% and 17% of patients, respectively. The most common TRAEs were fatigue (15%) and pruritus (15%) with monotherapy and pruritus (17%) and rash (14%) with combination therapy. Confirmed ORR was 0% with monotherapy and 7% with combination therapy. In part B, 39 patients had anti-PD-1 (programmed cell death protein 1)/PD-L1 (programmed death-ligand 1)-naive NSCLC (all received combination therapy), and 67 had anti-PD-1/PD-L1-refractory NSCLC (monotherapy, 34; combination therapy, 33). In patients with anti-PD-1/PD-L1-naive NSCLC: 85% had TRAEs-the most common were pruritus (38%) and hypoalbuminemia (31%); confirmed ORR was 26%, with responses occurring in both PD-L1-positive and PD-L1-negative tumors. In patients with anti-PD-1/PD-L1-refractory NSCLC: 56% receiving monotherapy and 70% receiving combination therapy had TRAEs-the most common were rash and fatigue (21% each) with monotherapy and pruritus (36%) and fatigue (24%) with combination therapy; confirmed ORR was 3% with monotherapy and 3% with combination therapy. CONCLUSIONS: Vibostolimab plus pembrolizumab was well tolerated and demonstrated antitumor activity in patients with advanced solid tumors, including patients with advanced NSCLC.

High-dose chemotherapy with autologous stem cell transplantation in relapsed or refractory germ cell tumours: outcomes and prognostic variables in a case series of 17 patients.

BACKGROUND: Optimal therapy for men relapsing after initial chemotherapy for germ cell tumours (GCT) is poorly defined. Both conventional dose salvage regimens and high-dose chemotherapy with autologous stem cell transplantation (HDCT-ASCT) have been utilised. AIMS: To examine patients who received HDCT-ASCT for relapsed GCT within a single Australian centre. METHODS: Records between 2000 and 2012 were analysed for baseline characteristics, treatment-related toxicity and survival. Prognosis at the time of HDCT-ASCT was classified according to the International Prognostic Factors Study Group (IPFSG). RESULTS: Seventeen patients received HDCT-ASCT, median age 34 (21-46), with 41% having primary refractory disease and 53% with high/very high risk disease by IPFSG. The most common regimen utilised was paclitaxel/ifosfamide followed by high-dose carboplatin/etoposide (TI-CE; n = 12). The median duration of grade 4 (G4) neutropenia was 11 days (range 9-17) with febrile neutropenia in 90% resulting in four intensive care unit admissions (8%). Median duration of G4 thrombocytopenia was 10 days (range 8-19) requiring a median of two pooled platelets bags (range 0-33) per episode. Transplant-related mortality occurred in one patient (veno-occlusive disease). Twenty-seven per cent of HDCT-ASCT cycles were associated with grade 3 mucositis (median total parenteral nutrition days = 5 (0-23)). Two-year progression-free survival (PFS) and overall survival (OS) rates were 59% and 71%. Patients who received HDCT-ASCT as second or subsequent relapse fared worse than those treated with HDCT-ASCT at first relapse (hazard ratio 0.23 (95% confidence interval: 0.04, 1.37; P-value 0.09). Three-year OS for those who received TI-CE at first relapse was 90%. CONCLUSIONS: HDCT-ASCT for relapsed GCT is effective with acceptable toxicity. There was encouraging PFS/OS, particularly in a poor-prognosis cohort.

An initial watch and wait approach is a valid strategy for selected patients with newly diagnosed metastatic colorectal cancer.

BACKGROUND: A range of treatments are available for patients with metastatic colorectal cancer (mCRC). An initial period without active treatment, a 'watch and wait approach', is variably employed in routine practice; however, there is no data to support this approach. PATIENTS AND METHODS: We prospectively collected data regarding clinician treatment recommendations for patients with newly diagnosed mCRC in addition to subsequent treatment and outcomes. Follow-up and management was according to standard protocols. RESULTS: Seven hundred and thirty-six patients (59.1% male, 40.9% female) with mCRC (January 2003-December 2010) were analysed; the median age was 67.9 years (range 26.2-95.5). Three hundred and seventy-seven patients (51.2%) received immediate chemotherapy. For 133 (18.1%), treatment was considered inappropriate. 34 patients (4.6%) declined therapy. For 192 (26.1%), a watch and wait policy was adopted and 168 (87.5%) of these received treatment, at a median of 3.7 months (range 2-35 months) from diagnosis. Compared with patients immediately treated, the number receiving all active chemotherapy agents (30.4 versus 39.3%) was similar and median survival (27 versus 17 months, P = 0.0008) was superior. CONCLUSIONS: Our study demonstrates that a substantial minority of patients underwent an initial watch and wait approach. Ultimately, they received a similar treatment exposure to patients treated immediately and the survival outcomes were not compromised.