DISCUSSION
NSCLC, toxicities, human venous blood samples, tumor
TUMOR, NSCLC
A randomized, Phase II study of pemetrexed plus bevacizumab versus pemetrexed alone after treatment with cisplatin, pemetrexed, and bevacizumab in untreated advanced non‐squamous, NSCLC was conducted. To the best of our knowledge, this is the first study to demonstrate the significant progression free survival benefit of adding bevacizumab in maintenance therapy after induction therapy with cisplatin, pemetrexed, and bevacizumab for non‐squamous NSCLC. In addition, although this was a small‐sample analysis, this is the first study to have assessed immune‐suppressive cells of human venous blood samples in advanced NSCLC patients treated with chemotherapy including a VEGF inhibitor.This study showed that the addition of bevacizumab to pemetrexed in maintenance therapy prolonged PFS significantly. In the PARAMOUNT study, which was a Phase III, randomized study comparing pemetrexed with placebo in maintenance therapy, the median PFS of maintenance therapy with pemetrexed alone was 4.1 months.Recently, the addition of immune checkpoint‐inhibitors to platinum‐based chemotherapy showed significant survival benefits over chemotherapy alone in advanced, non‐squamous NSCLC.Some previous studies could not show sufficient data to support the OS benefit of the addition of bevacizumab to platinum‐based chemotherapy in the treatment of advanced, non‐squamous NSCLC. However, we have often experienced cases in which platinum‐based chemotherapy with bevacizumab is highly effective. The present study has limitations in assessing OS. This is because OS is not included in the primary endpoint and the number of cases is small to assess OS. In the present study, OS tended to be similar in the Pgroup and the PBgroup. However, when the response to induction therapy was PR, the median OS tended to be longer in the PBgroup than in the Pgroup. When the response to induction therapy was SD, the median OS tended to be similar in the PBgroup and the Pgroup. In the present study, the evaluation of PR to induction therapy needed to confirm a response duration of 4 weeks. Therefore, the tumor reduced clearly within two cycles of induction therapy in patients with PR. Many previous studies of advanced NSCLC have not shown that the addition of bevacizumab could prolong OS significantly.Recently, VEGF has been found to increase and activate immunosuppressor cells, such as MDSCs and Tregs, and their effects.In conclusion, a randomized, Phase II study comparing maintenance therapies of pemetrexed plus bevacizumab versus pemetrexed alone after treatment with cisplatin, pemetrexed, and bevacizumab was conducted. The addition of bevacizumab to pemetrexed in maintenance therapy after treatment with cisplatin, pemetrexed, and bevacizumab is effective with tolerable toxicities in untreated, advanced, non‐squamous NSCLC. The potential effects of bevacizumab on immune function were also suggested. Therefore, bevacizumab should be considered in combination with cisplatin, pemetrexed, and immune checkpoint‐inhibitors. In addition, early PR to induction therapy and pretreatment M‐MDSC counts in peripheral blood may be related to the survival benefit of the addition of bevacizumab to the combination of cisplatin and pemetrexed.