Abstract
The BEVA2007 study is a multistep phase I-II trial aimed to investigate in advanced NSCLC patients the safety, the immunobiological and the antitumor activity of the mPEBev, an original metronomic chemo-biological regimen whose results showed significant antiangiogenic and immune-modulating and antitumor activity. Eighty-six advanced NSCLC patients (76 males and 10 females; 53, adenocarcinoma; 13 squamous carcinoma; and 20 with different subtypes) were enrolled between September 2007 and September 2015. All of them received cisplatin (30mg/sqm, days 1-3q21), oral etoposide (50mg, days 1-15q21) and bevacizumab 5mg/kg on the day 3q21 (mPEBev regimen). There were two cases of fatal bleeding after 3 and 4 treatment courses, and five cases of severe infections fully recovered with medical treatment. Hematological toxicity [grade 1-3 leukopenia (25%), anemia (25%)], g 1-2 gastroenteric toxicity (10%) and alopecia (50%) were the most common adverse events. There was a partial response in 54 cases (62,8%) and a stable disease in 9 cases (10,5%) with a mean progression free survival (PFS) and overall survival (OS) of 13.46 (8.39-18.54) and 20.57 (14.5-26.6) months, respectively. Log-rank tests, revealed a longer survival in patients with baseline levels of Neutrofil to lymphocyte ratio (NLR) [L vs. H= 24.9 vs. 8.9 months, P=0.033], IL17 [L vs. H= 32.9 vs 11 months, P=0.033], leptine [L vs. H= 30,5 vs 8,5 months, P=0,025] and Tregs [L vs. H= 35.37 vs 9.9 months, P=0.049] lower than median value of each specific parameter. A longer survival was also found in patients with a treatment related fold increase to baseline > 1 in CD4+/CD8+ t cell ratio and DCs expressing CD83 [L vs H 8.4 vs 20.85 months, P=0.05 ] and CD80 [L vs H = 8 vs 23 months, P=0.046]. These results suggest that both systemic Inflammatory status and treatment-related immunomodulation may affect the outcome of these patients a finding that highlight a possible involvement of immunesystem in ultimate antitumor effect of this regimen, and offer a solid rationale to test our metronomic regimen in a module of sequential combination with anti-PD-1/PDL-1 inhibitors.
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