Background T-cell trafficking to the tumor is inhibited via vascular endothelial growth factor (VEGF)-mediated down-regulation of important adhesion molecules on tumor-associated blood vessels and progression of disease on immune checkpoint blockers (ICBs) has been associated with decreased tumor-infiltrating immune cells.1 2 We hypothesized that inhibiting VEGF signaling through its receptor, VEGFR2, would increase intratumoral T cells. Therefore we sought to evaluate the combination of ramucirumab, an anti-VEGF receptor 2 monoclonal antibody, and atezolizumab in patients with advanced-stage, non-small cell lung cancer (NSCLC) patients who have previously progressed on at least one line of ICB. Here, we report on the first twelve patients enrolled on trial.
Methods Advanced stage NSCLC patients with an ECOG performance status of ≤1 who had previously been treated with ICBs were eligible with no limitation on prior lines of ICB therapy. Patients with untreated brain metastasis, recent hemoptysis, gastrointestinal bleeding or perforation or fistula were excluded. The study was conducted with a two-stage MiniMax design. Peripheral blood and repeated biopsy, when feasible, were collected for correlative analysis.
Results Twelve patients were enrolled in the first stage of the trial. The median age was 68 (range 47-78), 10 of the patients are female, and 10 had non-squamous histology. Patients had an average of 3.5 prior lines of therapy and 1.6 lines of prior immunotherapy. Overall, treatment was well-tolerated with no grade 3 or 4 adverse events. The most common adverse events were grade 1 or 2 hypertension (35%), nausea (25%) and vomiting (25%). There were no objective responses and 11 patients (91%) achieved stable disease. The median progression-free survival is 3 months with 3 patients (25%) on trial for more than 12 months. The median overall survival (OS) at the time of the latest data cutoff on 9/15/20 is 11.5 months.
Conclusions The preliminary data from our study showed that combination of ramucirumab and atezolizumab is well-tolerated and associated with prolonged overall survival in a subset of heavily pretreated patients who progressed on prior ICB. The trial is still accruing patients and exploratory analyses are planned.
Ethics Approval The study was approved by the Washington University Institutional Review Board.
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Herbst RS, Soria JC, Kowanetz M, et al. Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients. Nature 2014;515(7528):563-567.
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